Nanoparticles in Tumor Microenvironment Remodeling and Cancer Immunotherapy

Lu et al.
Journal of Hematology & Oncology (2024) 17:16 Journal of Hematology &

https://doi.org/10.1186/s13045-024-01535-8
Oncology
REVIEW Open Access
Nanoparticles in tumor microenvironment

remodeling and cancer immunotherapy
Qiang Lu1†, Dongquan Kou2†, Shenghan Lou3†, Milad Ashrafizadeh4,5,6, Amir Reza Aref7,8, Israel Canadas9, Yu Tian10,
Xiaojia Niu11, Yuzhuo Wang11, Pedram Torabian12,13, Lingzhi Wang14,15, Gautam Sethi14,15*, Vinay Tergaonkar16,
Franklin Tay17, Zhennan Yuan18* and Peng Han18,19*
Abstract
Cancer immunotherapy and vaccine development have significantly improved the fight against cancers. Despite
these advancements, challenges remain, particularly in the clinical delivery of immunomodulatory compounds.
The tumor microenvironment (TME), comprising macrophages, fibroblasts, and immune cells, plays a crucial role
in immune response modulation. Nanoparticles, engineered to reshape the TME, have shown promising results
in enhancing immunotherapy by facilitating targeted delivery and immune modulation. These nanoparticles can
suppress fibroblast activation, promote M1 macrophage polarization, aid dendritic cell maturation, and encourage
T cell infiltration. Biomimetic nanoparticles further enhance immunotherapy by increasing the internalization
of immunomodulatory agents in immune cells such as dendritic cells. Moreover, exosomes, whether naturally
secreted by cells in the body or bioengineered, have been explored to regulate the TME and immune-related cells
to affect cancer immunotherapy. Stimuli-responsive nanocarriers, activated by pH, redox, and light conditions,
exhibit the potential to accelerate immunotherapy. The co-application of nanoparticles with immune checkpoint
inhibitors is an emerging strategy to boost anti-tumor immunity. With their ability to induce long-term immunity,
nanoarchitectures are promising structures in vaccine development. This review underscores the critical role of
nanoparticles in overcoming current challenges and driving the advancement of cancer immunotherapy and TME
modification.
Keywords Bioengineered nanostructures; cancer immunotherapy, Immune evasion nanoparticles, Tumor
microenvironment
Introduction
Cancer cells are mainly suppressed by the complicated
networks in the immune system, but tumors develop
several mechanisms to evade anti-cancer immunity [1].
†
Qiang Lu, Dongquan Kou and Shenghan Lou contributed equally
Hence, cancer immunotherapy has been introduced as a
to this work.
new mainstay to utilize the patient’s own immune system
*Correspondence:
Gautam Sethi
in cancer cell eradication. The cancer immunotherapy
[email protected] concept can be categorized into immune checkpoints-
Zhennan Yuan targeted therapy and the adoptive transfer of manipu-
[email protected]
Peng Han
lated immune cells. Both of these strategies contribute
[email protected] to improving the immune system’s function in the iden-
Full list of author information is available at the end of the article tification and eradication of cancer cells [2]. A number of
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Lu et al. Journal of Hematology & Oncology (2024) 17:16 Page 2 of 48
immune checkpoint inhibitors, including programmed [16, 17]. Regarding solid tumors, antigen uptake and
cell death ligand 1 (PD-L1) or cytotoxic T-lymphocyte- presentation are mainly performed by macrophages and
associated protein 4 (CTLA-4) antibodies and agonists of dendritic cells [18]. Although macrophages are the prev-
costimulatory molecules have shown satisfactory results alent phagocytic cells in cancers, they lack the ability to
in clinics for the treatment of cancer patients, however, migrate into lymph nodes and activate T cells [18]. Note-
they still have a number of troublesome problems includ- worthy, macrophages are considered a factor in impair-
ing low response rate, high cost and non-specific toxicity ing the T cell-mediated responses against tumors, and
[3–5]. Another method is the adoptive transfer of cells, they reduce the response to immune checkpoint block-
which uses genetically engineered cells such as chimeric ade, chemotherapy, and radiotherapy [19, 20]. On the
antigen receptor (CAR)-T cells and others such as multi- other hand, the dendritic cells have a significant ability
potent mesenchymal stem cells to affect the expression of in lymph node migration to induce T cells for immunity
a specific cytokine and other features of cells [6, 7]. Since [18, 21–24]. Moreover, increasing evidence has shown
the promising application of immune checkpoint block- the ability of tumor-resident dendritic cells to stimulate T
ade and CAR-T cell therapy, cancer immunotherapy has cell-mediated anti-cancer immune response [18, 24–28].
undergone significant advances. Cancer immunotherapy However, it should be noted that macrophages and other
is now considered a powerful and innovative strategy in cells in the TME, including fibroblasts, can exert carci-
clinics compared to other conventional treatments such nogenic activity upon induction and their regulation is
as surgery, radiotherapy, and chemotherapy. The most of importance for maximizing cancer immunotherapy
recent immunotherapeutic methods have utilized T cells [19, 29–36]. Stimulation of TME remodeling represents
for the induction of adaptive immune responses. On the a beneficial strategy for cancer treatment and immuno-
other hand, studies have shown that a number of innate therapy [37–43]. Although a significant number of stud-
immune checkpoints with expression on the antigen- ies advocate the potential of immunotherapy in cancer
presenting cells (APCs) contribute to immune evasion. suppression [44–48], immunotherapy has faced its own
These checkpoints are capable of detecting and eradicat- problems, and the most prominent one is immune eva-
ing tumor cells through phagocytosis and suppressing sion. Regarding the mutations and dysregulation of
innate immune response. The first line of the immune molecular pathways in human tumors, the oncogenic
defense system is provided by innate immune cells such pathways are activated, which can finally promote the
as macrophages, monocytes, and dendritic cells that act survival of cancer cells and mediate their escape from
as APCs. They induce pro-inflammatory reactions to cancer immunotherapy and immune surveillance.
foreign attacks and contribute to the repair of damaged In addition to immune resistance, current drugs
tissues. The cancer cells are able to express a number of used for cancer immunotherapy and TME remodeling
signals known as “do not eat me” signals through expres- lack targeting features. As a result, the nanoparticles
sion of CD47 [8], CD24 [9], PD-L1 [10], the beta-2 micro- have been introduced to facilitate anti-cancer immu-
globulin (β2M) subunit of MHC-I [11], stanniocalcin nity. Nanostructures can improve the retention time
1 (STC-1) [12] and GD2 [13] to evade the macrophage- and provide the targeted delivery [49]. Furthermore,
mediated phagocytosis. nanoparticles are capable of TME remodeling to dis-
The application of cancer immunotherapy has been of rupt an immunosuppressive environment. The distor-
importance in the treatment of both hematological and tion of blood vessels and high growth rate of tumor cells
solid tumors [14]. In fact, immunotherapy has revolu- cause hypoxia in TME that mediates an immunosup-
tionized cancer therapy, and it aims to apply immune pressive environment, characterized by an increase in
checkpoint inhibitors, adoptive cell therapy, and vaccines the accumulation of immunosuppressive cells, includ-
to finally target the immune-oncology cycle for improving regulatory T cells (Tregs) and myeloid-derived sup-
ing the activity of T lymphocytes in tumor suppression. pressor cells (MDSCs), as well as secretion of a number
All of these regimens should be applied in a cycle to of factors including vascular endothelial growth fac-
accelerate the tumor antigen presentation by APCs [15]. tor (VEGF) and transforming growth factor β (TGF-β).
APCs are the cells with the ability to capture, process, As a result, the function of dendritic cells is suppressed
and present the exogenous antigens to T cells, and are and macrophages are polarized into M2 phenotype. The
primarily recognized through the expression of MHC- nanoparticles can be specifically developed to target
II and other co-stimulatory molecules. APCs are mainly TME components and disrupt the immunosuppressive
comprised of dendritic cells, macrophages, and B cells. TME to improve the function in cancer immunotherapy.
There are also other cells with expression of MHC-II Moreover, nanoparticles can be considered as nano-scale
such as thymic epithelial cells. Moreover, there are also delivery systems for drugs [50]. They can selectively accu-
other kinds of cells, such as eosinophils and basophils, mulate in tumor tissue and enhance the retention time of
with the ability of MHC-II expression upon stimulation drugs. Moreover, nanostructures demonstrate enhanced
permeability and retention (EPR) effect, improving their focuses on the application of nanoparticles for TME
accumulation in tumor sites because of leaky tumor vas- remodeling and boosting cancer immunotherapy. The
culature and damaged lymphatic drainage [51, 52]. Fur- current review will first provide a comprehensive outline
thermore, nanostructures can be functionalized with regarding TME components and then, immune evasion is
ligands, to specifically target the tumor and even the discussed. Then, the potential of nanoparticles for TME
TME components [53–55]. As a result, nanoparticles re-education through targeting its components, includ-
have been introduced as new structures for potentiating ing macrophages, is described. Moreover, biomimetic
cancer immunotherapy and overcoming immune evasion nanoparticles and their stimuli-responsive kinds for bet-
[56–63]. ter tumor targeting are described. Since exosomes have
Amidst the current challenges in cancer immunother- emerged recently in cancer immunotherapy, the role of
apy, the need for improving cancer immunotherapy, and exosomes, both endogenous and bioengineered, in the
the promise of nanoparticles, the use of targeting sys- regulation of the immune system for tumor suppres-
tems has emerged as a novel strategy for immunotherapy sion is discussed. Figure 1 provides an overview of using
enhancement and TME remodeling. The development nanoparticles for cancer immunotherapy.
of nanoparticles based on targeting TME and improv-
ing cancer immunotherapy can strengthen the potential Tumor microenvironment components
for tumor eradication. Since the TME modulators suf- Macrophages
fer from targeted action, it is preferred to use targeted Macrophages, renowned for their phagocytic nature, play
non-scale delivery systems for the regulation of TME and a crucial role in the immune system. They participate in
improving cancer immunotherapy. The present review various physiological processes, including development
Fig. 1 An overview of using nanoparticles in cancer immunotherapy. The nanoparticles circulate in blood, and upon reaching the tumor site, they re-
educate several tumor microenvironment components, including cancer-associated fibroblasts and tumor-associated macrophages, to finally activate
the immune system. Moreover, nanoparticles can stimulate immunogenic cell death to enhance the maturation of dendritic cells for the activation of
immune cells, such as T cells, to enhance cancer immunotherapy. The co-application of nanoparticles with immune checkpoint inhibitors, such as PD-L1
blockers, can augment the potential of cancer immunotherapy
and homeostasis. The phenotype and function of mac- alterations and signaling network changes that acceler-
rophages are intricately determined by their origin and ate tumor development [85]. Under specific conditions,
polarization [64]. Initially believed to originate from CAFs may exhibit anti-cancer activities, contributing to
hematopoietic stem cells and circulating monocytes [65], tumor suppression [86].
the recent studies reported that macrophages have an The heterogeneity of CAFs arises from their diverse
embryo-derived lineage, with precursors derived from origins, including normal fibroblasts, epithelial cells,
erythro-myeloid progenitors in yolk sacs and fetal liver endothelial cells, peritumoral adipocytes, pericytes,
[65, 66]. Maintaining or enhancing the macrophage pop- hematopoietic stem cells, mesenchymal stem cells, and
ulation is essential for these cells to function effectively cancer stem cells [87]. Based on their functions, CAFs
[67, 68]. There are two strategies for the replenishment of may be categorized into two groups: carcinogenic and
macrophages: monocyte recruitment and increased pro- anti-carcinogenic CAFs [88, 89]. Ohlund and colleagues
liferation in the form of tissue-resident macrophages for identified two distinct subtypes of CAFs in pancreatic
elevating self-renewal ability [67, 69]. cancer: myofibroblasts (myCAFs) and inflammatory
In the TME, macrophages are referred to as tumor- CAFs (iCAFs) [90]. The myCAFs, located near cancer
associated macrophages (TAMs), constituting 50% of the cells, are stimulated by transforming growth factor-beta
tumor mass [70]. The TAMs engage in intricate interac- (TGF-β) and exhibit high levels of alpha-smooth muscle
tions not only with cancer cells but also with natural killer actin (α-SMA). In contrast, iCAFs are positioned fur-
(NK) cells, T cells, endothelial cells, and fibroblasts. The ther away from cancer cells. They demonstrate elevated
roles of TAMs extend to the regulation of cancer prolifer- α-SMA levels and the ability to secrete IL-6 and leukemia
ation, invasion, and angiogenesis [71–73]. Macrophages inhibitory factor [91].
have also been associated with the development of resis- Another subclass of CAFs, antigen-presenting CAFs
tance to cancer therapies [74]. The TAMs primarily origi- (apCAFs), express biomarkers related to the MHC-II
nate from the bone marrow or the yolk sac [75]. They can class and CD44, enabling them to stimulate CD4+ T cells
be polarized into two phenotypes. The M1 macrophages, in an antigen-dependent manner [92]. Additionally, there
induced by lipopolysaccharide and type 1 T helper cell is a subtype known as restraining CAFs (rCAFs). Each of
(Th1)-derived cytokines, exhibit pro-inflammatory these subpopulations plays a distinct role in cancer. For
and anti-cancer functions [76]. The M2 macrophages, example, iCAFs and myCAFs contribute to metabolic
induced by Th2-derived cytokines like interleukin-4 (IL- reprogramming and angiogenesis in cancer, respectively.
4), IL-10, and IL-13, promote proliferation, invasion, and The iCAFs can secrete growth factors, cytokines, and
angiogenesis [76]. A delicate balance exists between M1 chemokines, including PD-L1/L2, Fas ligand, and oth-
and M2 macrophages in vivo, influencing tumorigenesis ers, that influence the regulation of the immune system.
and treatment outcomes [77, 78]. The anti-inflammatory The myCAFs, on the other hand, contribute to extracel-
nature of M2 macrophages accelerates cancer progres- lular matrix remodeling by enhancing collagen synthesis.
sion. The regulation of TAMs has been of importance The apCAFs are involved in stimulating CD4+ T cells for
for cancer immunotherapy. Currently, the strategies immune cell regulation, while rCAFs exhibit the ability to
for targeting TMAs are based on controlling the ori- suppress tumorigenesis [93]. Regarding the importance
gin, functional polarization, and phagocytic function of of CAFs in tumorigenesis, targeting CAFs for cancer
TAMs. Moreover, macrophages and monocytes have immunotherapy has been of importance. The nanostruc-
been engineered to mediate anti-cancer immunity. For tures demonstrate high penetration and permeability in
this purpose, four distinct strategies have been exploited, tumor sites, and can be utilized to regulate CAFs [94].
including a decrease in TAM population, switching from Moreover, nanoparticles can be utilized to engineer
M2 polarization into M1 phenotypes, controlling mac- CAFs to act as APCs and stimulate antigen-specific CD8+
rophage phagocytic signal, and bioengineering of mac- T cells in cancer immunotherapy [95]. Nanostructures
rophages for increasing phagocytosis [79]. Currently, the can trigger clearance of activated and senescent CAFs
nanostructures have been widely applied to re-educate [96], and regulation of CAFs by nanoparticles can disrupt
TAMs [80], change phagocytosis ability [81], suppress cancer metastasis and invasion [97].
TAMs [82] and deliver drugs to TAMs [83] for cancer
immunotherapy. Neutrophils
Up to 70% of circulating leukocytes are comprised of neu-
Cancer-associated fibroblasts trophils [98], and are considered a first-line against patho-
Cancer-associated fibroblasts (CAFs) represent a diverse gens [99]. Neutrophils have a short life and can persist in
group of cells that infiltrate the TME. The CAFs are dis- circulation for five days [100]. When there is tissue dam-
tinct from normal fibroblasts [84]. These cells play a age or infection, the epithelial cells secrete chemokines
pivotal role in tumorigenesis by inducing biochemical to recruit neutrophils. Upon this, neutrophils extravasate
the blood circulation, enter damaged tissue to secrete Upon maturation, NK cells migrate from the bone mar-
a number of inflammatory cytokines, release neutro- row to the blood and subsequently reside in peripheral
phil extracellular traps (NETs), and finally, phagocytose tissues. Because of their capacity to move between lym-
the pathogens or invading microorganisms [101]. NETs phatic and non-lymphatic tissues, NK cells are distrib-
are vehicles for anti-microbial peptides and toxins [102, uted in numerous organs and tissues [122–124]. Mature
103]. In cancer, there are two categories of tumor-associ- NK cells acquire the capability to exert cytotoxic impacts
ated neutrophils (TANs) similar to the Th1/Th2 pattern, on cancer cells or virus-infected cells [125]. Serving as
including N1 and N2 with tumor-suppressor and tumor- contributors to the adaptive immune system, NK cells
promoting function, respectively. Tumor type and stage interact with other immune cells through the secretion of
determine the phenotype of neutrophils in TME. During cytokines, growth factors, and chemokines [125]. These
the first stages of tumorigenesis, neutrophils demonstrate effects position NK cells as effective effectors in diseases
an inflammatory phenotype, and as the cancer advances, such as cancer, infectious diseases, autoimmunity, and
the neutrophils achieve an immunosuppression pheno- chronic inflammation [126–129].
type [104]. Neutrophil-mediated inflammation regula- Moreover, NK cells play a significant role in the innate
tion relies on the secretion of ROS and RNS. Moreover, immune system, providing surveillance in hemato-
the extracellular matrix can be re-configured by the logical cancers and cancer metastasis [110, 130, 131].
neutrophils through the secretion of neutrophil elastase The increased infiltration of NK cells into the TME is
and matrix metalloproteinases. The neutrophils display positively associated with the prognosis of various can-
the ability to stimulate angiogenesis through oncostatin- cer types, including melanoma, renal cell cancer, liver
M, increase carcinogenesis through PGE2, and enhance tumors, and breast cancer, among others [132–136].
metastasis of cancer through the release of ROS, RNS, The adaptive immune system is primarily shaped by T
NE and MMP-9. Noteworthy, the NETs have consisted of cells, providing effective defense against pathogens and
MMPs, cathepsin G, and NE [105, 106]. The function of cancers. Upon exposure to cytokines and co-stimulatory
these proteases is to mediate pro-inflammatory cytokine signals, naïve T cells undergo proliferation, differentiat-
degradation and re-accumulate in TME for enhancement ing into effector cells. Naïve CD4+ T cells can differenti-
in tumorigenesis and metastasis [107]. In cancer patients, ate into T helper cells, including TH1, TH2, TH17, and
the plasticity of circulating neutrophils is of importance, TFH cells, to exert immune functions. The differentiation
known as high-density neutrophils (HDNs) or low-den- of naïve CD8+ T cells into effective CD8+ T cells enables
sity neutrophils (LDNs), corresponding to N1 and N2 these cells to combat infections and cancers through the
phenotypes, respectively. LDNs that have an immature release of IFN-γ, TNF-α, and cytotoxic molecules [137].
phenotype, show prevalence in the circulation of many A challenge in cancer arises from T cell exhaustion.
cancers and participate in carcinogenesis and metastasis This phenomenon is mediated by various mechanisms,
[100]. In the field of cancer immunotherapy, the stimula- with the PD-1 axis being the most prominent. Upon anti-
tion of N1 neutrophils can mediate toxic impacts on can- gen exposure, naïve T cells transform into effector T cells,
cer cells [108]. Furthermore, the stimulation of Ly6Ehi with some undergoing cell death and others participat-
neutrophils through the STING pathway can enhance ing in tumor elimination. Antigen presentation can lead
sensitivity to anti-PD-1 therapy, and they can be utilized to the formation of stem cell memory T (TSCM) cells,
as predictors of cancer immunotherapy [109]. Therefore, which convert into TCM, TEM, and TRM. The TRM
the development of nanoparticles for targeting neutro- cells reside in the tissue, ready to respond to secondary
phils in cancer immunotherapy is important. stimulation, while TSCM and TCM possess self-renewal
capacity, generating TEM and TE upon re-stimulation
Natural killer cells and T cells [138].
As innate lymphocytes, NK cells exhibit a shorter half-life Signs of T cell exhaustion include the expression of
compared to B and T cells, necessitating their replenish- inhibitory receptors, reduction in T cell function, and
ment from bone marrow progenitors [110]. The NK cells decreased proliferation. Exhausted T cells exhibit a
undergo linear differentiation, with highly proliferative unique epigenetic profile that may result in a differen-
immature NK cells differentiating into fully functional tial or poor response to immunotherapy. Additionally,
and granular effectors [111–113]. Enhancing the fre- exhausted T cells experience metabolic dysregulation,
quency, infiltration, and function of NK cells contributes including mitochondrial suppression and glycolysis inhi-
to the improved survival of cancer patients [114–117]. bition [139]. The challenge in cancer therapy extends
This renders NK cells valuable in cancer immunotherapy. beyond T cell exhaustion, as their death and reduced
These group I innate lymphoid cells can rapidly target proliferation can impair immune reactions. Targeting
cells without prior sensitization [118], and express T-bet NK and T cells with nanoparticles has strengthened can-
and Th1-related cytokines, including IFN-γ [119–121]. cer immunotherapy. The nanoparticles with high uptake
in NK cells, such as lipid-based nanoparticles, can be [163, 164], recent advances have illuminated their roles in
utilized to engineer NK cells [140]. Furthermore, nano- both physiological and pathological conditions.
structures can be utilized for non-invasive tracking of Pericytes play a crucial role in regulating blood vessel
NK cells, including their migration and biodistribution development and modulating blood flow, coagulation,
in tumor regions [141]. The expression levels of CCR4 and vascular permeability [165]. The structure of capil-
and CXCR4 on the surface of NK cells can be changed laries includes endothelial cells, pericytes, the basement
by nanoparticles to improve their interaction with can- membrane, and vascular smooth muscle cells [166]. The
cer cells [142]. Noteworthy, the nanoparticles can be primary function of pericyte function in cancer progres-
designed to stimulate both NK and CD8+ T cells in can- sion is stimulating angiogenesis in the TME [167]. The
cer immunotherapy [143]. CD248 is capable of Wnt upregulation and increasing
the levels of OPN and SERPINE1 in pericytes to cause
Endothelial cells and pericytes angiogenesis and expedite cancer progression [168].
Endothelial cells form the inner lining of blood vessels. Additionally, pericyte contractility can be induced by the
The biological functions of endothelial cells are crucial enzyme hexokinase 2 in glycolysis, leading to abnormali-
for preserving normal physiological conditions [144]. ties in tumor blood vessels [169]. When present in the
These cells play important roles in regulating blood clot- tumor site, RGS5-TGFβ-Smad2/3 creates an anti-apop-
ting, vessel size, and immune functions to enhance blood totic environment that accelerates cancer cell growth
fluidity, oxygen distribution, cell transport, and nutri- [170]. Figure 2 is a schematic representation of TME
ent supply. Endothelial cells continuously secrete anti- components.
coagulant proteins to prevent clotting in vascular beds,
maintaining homeostasis and ensuring blood flow and Myeloid-derived suppressor cells
pressure at an appropriate level to deliver oxygen and The Myeloid-derived suppressor cells (MDSCs) are
nutrients to tissues [145–149]. another type of cell present in TME. There are a num-
Despite their essential physiological functions, endo- ber of arguments that MDSCs are a subtype of neutro-
thelial cells have been implicated in cancer progression. phils [104] due to the presence of overlapping markers
Recent reviews have highlighted the role of endothelial among MDSCs and TANs, making it challenging and
cells in the tumor stroma [150, 151]. In the initial stages, problematic to distinguish them. There is still contro-
endothelial cells induce angiogenesis to increase the pres- versy regarding whether MDSCs represent a separate
ence of blood vessels in the primary tumor. These cells lineage of cells or are polarized immature neutrophils
also function as a platform and site for membrane-bound [171]. Overall, MDSCs are considered a heterogeneous
factors and proteins, creating a TME conducive to can- population of cells with myeloid origin [172]. In spite of
cer progression. These localized functions of endothelial origination from myeloid progenitor cells, MDSCs and
cells also play a role in regulating angiocrine signaling at TANs are considered different cell types. Furthermore,
distant sites, influencing organ function. Furthermore, MDSCs demonstrate several distinct features from neu-
factors and proteins secreted by tumor cells can extend trophils, including downregulation of CD16 and CD621
beyond tumor boundaries, affecting endothelial cells at and upregulation of Arg1, CD66B, and CD11b [173, 174].
distant sites and exerting systematic functions [152]. Furthermore, the studies have shown other subtypes
Understanding the functions and regulatory impacts of MDSCs including monocytic MDSCs (M-MDSCs),
of tumors beyond their sites is crucial, given that most which are distinguished by a CD11b hi, LY6C hi, and
cancer-related deaths result from invasion, thrombosis, LY6G lo phenotype, polymorphonuclear MDSCs (PMN-
and cachexia [153–155]. Proteins and factors secreted MDSCs), which display a CD11b hi, LY6C lo, and LY6G
by tumor cells can induce changes in endothelial cells in hi phenotype, and early stage MDSCs (eMDSCs) which
the pre-metastatic niche, enhancing the dissemination are CD13- and CD14-, and CD33 + in humans [175, 176].
of cancer cells and mediating angiogenesis. Additionally, In TME, it is possible to observe both M-MDSCs and
these factors can lead to thrombosis in distant vascula- PMN-MDSCs, and compared to MDSCs, they demon-
ture [156]. Endothelial pericytes have been recognized strate a suppressive phenotype [177]. The MDSCs sup-
more than a century ago as microvasculature-associated press T cells and the innate immune system to create an
mural cells [157]. These perivascularly positioned cells immunosuppressive phenotype in TME [177]. MDSCs
[158–160] are ubiquitously distributed in all vascular- also contribute to the formation of pre-metastatic niches,
ized tissues [161, 162]. Identification of pericytes requires can elevate stemness and angiogenesis, and promote
immunostaining and the use of biomarkers and antigens metastasis through EMT induction and enhancing IL-6
to differentiate them from vascular smooth muscle cells, secretion [178, 179]. There are also other factors in TME
fibroblasts, and mesenchymal cells [157]. Initially consid- that can affect MDSCs. The HIF-1α, a marker of hypoxic
ered inert cells contributing to physical vascular stability TME, stimulates the differentiation of MDSCs into
Fig. 2 Cellular components that influence the tumor microenvironment (TME). Interactions within the TME play a crucial role in accelerating cancer
progression. Cancer cells activate the PD-L1/PD-1 axis, leading to T cell exhaustion and impairment of T cell function. In addition, cancer cell-secreted exo-
somes that carry PD-1 contribute to T cell dysfunction, reducing proliferation and hindering proper function. Natural killer cells counteract tumorigenesis
by secreting perforin and granular enzymes. Increased infiltration of Treg cells in the TME secretes TGF-β, inducing fibroblast transformation into cancer-
associated fibroblasts (CAFs), promoting extracellular matrix deposition, and causing T cell dysfunction. Myeloid-derived suppressor cells (MDSCs) induce
Treg cell formation in the TME through the secretion of PGE-2, IL-10, and TGF-β. Regulatory T cells (Treg), in turn, suppress the function of dendritic cells
(DCs) by secreting perforin, leading to DC cell apoptosis. M2-polarized macrophages secrete TGF-β and IL-10, disrupting DC cell function. The interaction
between endothelial cells and cancer cells results in angiogenesis, further enhancing cancer progression (created by Biorender.com)
TAMs with carcinogenic function [180]. The metabo- and pathological status, and various classes of cells,
lism of MDSCs in TME can be changed towards stimula- including adipocytes and tumor cells, can secrete them.
tion of fatty acid oxidation to enhance levels of Arg1 and The cytokines contribute to the cellular (type 1) and
NOS2 [181]. For cancer immunotherapy, the regulation antibody-mediated (type 2) immunity as anti/pro-
of MDSCs can provide new insights, such as the down- inflammatory and pro/anti-tumorigenic effectors that
regulation of CCRK that disrupts the immunosuppres- also rely on the TME. Cytokines can bind to the recep-
sion activity of MDSCs and promotes the potential of tor on the surface of other cells to regulate their action
immune-checkpoint blockade therapy [182]. The nano- and change the molecular pathways. There are different
structures are able to reduce the population and function kinds of cytokines in TME, including chemokines, inter-
of MDSCs, impair MDSC-mediated immunosuppression leukins, adipokines, transforming growth factors (TGFs),
and cause MDSC repolarization [183–185]. tumor necrosis factor (TNF), colony-stimulating factors
(CSFs), and interferons (IFN) that can act alone or in a
Cytokines, chemokines and other factors synergistic way to affect immune system [187]. Chemo-
The immune cells present in the TME use the cytokines kines are considered as chemoattractant cytokines for the
to send messages to other cells in an endocrine, para- recruitment of inflammatory cells, including leukocytes
crine or autocrine manner and provide intercellular (monocytes, neutrophils), along with other kinds of cells,
communication [186]. Cytokines, also known as immu- such as endothelial and epithelial cells [188]. Depending
nomodulatory agents, can be produced in physiological on the position of conserved cysteine residues, there are
various classes of cytokines including CX3C, CXC, CC, MHC I and II presentation, promoting the anti-cancer
or C chemokines [189]. Moreover, chemokines are able to immunity [203].
interact with the G protein-linked transmembrane recep-
tors known as chemokine receptors [190]. A number of Enzymes
chemokines, such as CXCL8 and CCL3, have an inflam- The changes in the expression level of enzymes are a fea-
matory function, and they recruit the cells via the inflam- ture of TME, and it can be exploited in a rational way to
matory signs or/and homeostatic [191]. Interleukins (ILs) treat cancer [204]. Enzymes are a kind of protein or RNA
possess a low molecular weight and demonstrate pro- that can facilitate chemical reactions [205]. The enzymes
and anti-inflammatory functions. The immunocompetent for catalyzing reactions are highly selective and under
cells, including T cells, granulocytes, monocytes, mac- mild conditions, demonstrate the specific substrates to
rophages, adipocytes, and endothelial cells, can secrete modulate biological and metabolic mechanisms [206].
ILs [192]. The ILs play a critical role in the development, The enzymes display a number of changes in expres-
differentiation, induction, maturation, migration, and sion in diseases such as TME [207]. The TME shows
adhesion of immune cells [193]. Adipokines (also known several enzyme secretions consisting of MMPs, hyal-
as adipocytokines) are cytokines that can be secreted by uronidase, γ-glutamyl transpeptidase, and esterase with
adipose tissue and consist of adipocytes, pre-adipocytes, higher expression in tumors compared to normal tissues
macrophages, stromal cells, fibroblasts, and endothe- [208, 209]. The proteases contribute to the degradation
lial cells [194]. The adipokines are comprised of adipose of proteins or peptide substrates. The oxidoreductases
tissue-specific cytokines (adiponectin, leptin) and other can mediate the catalysis of electron transfer from the
categories, including ILs, TNFs, and chemokines. More- reductant to the oxidant. Kinases provide phosphoryla-
over, inflammation, energy metabolism, and fat dis- tion to affect protein activity and phosphatases mediate
tribution can be controlled by adipokines [195]. The dephosphorylation. A number of enzymes demonstrate
adipokines also contribute to obesity-related inflamma- upregulation such as MMP-2 [210]. In bladder tumors,
tion to regulate metabolic diseases [196]. Adipocytes are the expression of HAse is enhanced compared to the nor-
critical regulators of tumorigenesis and metastasis [197]. mal tissues [211].
According to the impact of adipokines on the immune
system, there are two kinds, including pro-inflammatory, Extracellular matrix components
such as leptin, TNFα, interleukin-1β (IL-1β), interleu- The extracellular matrix (ECM) is comprised of colla-
kin-6 (IL-6), and interleukin-8 (IL-8), potentially linking gen, fibronection, laminin, vitronectin, elastin, and other
adiposity and inflammation, and anti-inflammatory, such factors including growth factors, cytokines, and matrix
as interleukin-10 (IL-10) and adiponectin [197, 198]. A metalloproteinases that contribute to the support of the
number of adipokines, such as adiponectin, demonstrate epithelial cell structure [212, 213]. Various cells have the
anti-carcinogenic function [198], while others, such as ability to secrete ECM components but they are mainly
leptin, demonstrate carcinogenic function [199]. TGFs secreted by fibroblasts [214]. During cancer progression,
are a number of protein hormones that are overexpressed ECM can be considered as an initiation factor. The com-
in human cancers and can modulate tumorigenesis and position of ECM can be different based on the type of
cancer growth. TGFα is a member of the EGF family cancer, such as gastric tumors, in which a lower degree
with the potential to regulate epithelial development and of differentiation improves the abundance of ECM com-
cell proliferation and can modulate carcinogenesis and ponents, heightens cell metabolism, and increases meta-
angiogenesis [200]. M2 macrophages and other kinds of bolic reprogramming [215]. According to the proteomic
cells, including cancer cells, can secrete TGF-β to modu- analysis, there is no difference between ECM compo-
late the function of T cells, NK cells, and macrophages nents in tumor and normal tissues, while their levels
present in TME, disrupting anti-cancer immunity and demonstrate changes that are manifested by enhance-
enhancing carcinogenesis [201]. IFN was discovered ment in ECM proteins and reduction in basement mem-
upon its function to interfere with viral growth [202]. The brane components modulating tumor angiogenesis,
host cells secret IFNs, and they can regulate the immune metastasis, and invasion [216]. The density of ECM com-
system. The fibroblasts and monocytes are able to secrete ponents increases during tumor progression, and a num-
type I IFNs such as IFN-α and IFN-β during the viral ber of factors, such as E-cadherin/β-catenin, demonstrate
attack. Then, the expression of proteins with the ability reduction, enhancing proliferation and metastasis of can-
to impair RNA and DNA replication is upregulated. The cer cells [217]. The increase in matrix density can cause a
type II IFNs, including IFN-γ can be released by CD8+ T kind of environmental stress to enhance carcinogenesis.
and Th1 cells to induce a number of cells, including NK The high-strength ECM can stimulate EMT to increase
cells, M1 macrophages, and CD8+ T cells for enhancing cancer progression and promote the infiltration of M2
polarized macrophages while it suppresses the function cells, offering potential in cancer immunotherapy [228].
of CD8+ T cells [218, 219]. While immune checkpoint inhibitors have significantly
improved tumor suppression and immunotherapy poten-
Hypoxia tial, the efficacy of these treatments is compromised by
The presence of hypoxia is another feature of TME result- mechanisms related to immune evasion.
ing from the high proliferation of tumor cells. The altera- In addition to the previously discussed mechanisms,
tions in interstitial fluid pressure, decrease in pH, and Choi and colleagues [229] proposed that lactic acid, a
enhancement in ROS generation can result from hypoxia byproduct of cancer cell metabolism, plays a crucial
[220]. In regions with hypoxia, there is high interstitial role in suppressing anti-cancer immunity. This hypoth-
fluid pressure due to leaky vasculature and abnormal esis has been substantiated by further research, notably
lymphatic drainage in the tumor [221]. Moreover, the in the comprehensive review by Wang and colleagues
hypoxia in TME can enhance the generation of lactic [230]. Their findings indicate that the accumulation of
acid and carbonic acid through glycolysis induction, pro- lactic acid and the resulting acidic tumor microenviron-
viding an acidic pH. The hypoxia-inducible factor (HIF) ment (TME) significantly impair anti-cancer immune
can induce carbonic anhydrase IX or XII to transform responses. Notably, it has been demonstrated that the
carbon dioxide and water into HCO3– that, upon diffu- presence of lactic acid and the acidic conditions within
sion out of the cell membrane, it enhances HCO3– lev- the TME inhibit the function of various immune cells,
els in TME. Furthermore, the endosomal and lysosomal including T cells and dendritic cells. This leads to an
vesicles in tumor cells demonstrate more acidic pH com- immunosuppressive environment that promotes tumor
pared to cytosolic pH [222]. The hypoxia TME displays growth and metastasis. Such insights underscore the
a redox potential difference between intracellular space complex interplay between cancer cell metabolism and
(reducing) and extracellular space (oxidizing). Such redox immune evasion, emphasizing the pivotal role of lactic
potential is vital for the development of smart and selec- acid and the acidic TME as key contributors to cancer
tive delivery of therapeutics [223]. The enzymatic reduc- progression.
tion during hypoxia in TME can cause the metabolism Upregulation of inhibitors such as SUSD6, TMEM127,
of chemical factors, including nitro, quinones, aromatic and WWP2 in MHC-I has been implicated in immune
N-oxides, aliphatic N-oxides, and transition metals [224]. evasion. Downregulation of SUSD6 increases MHC-I
Such a feature can be utilized to develop hypoxia-respon- antigen presentation, suppressing cancer progression in a
sive structures for exploiting the hypoxic regions [225]. CD8+ T cell-dependent manner. The mechanism involves
SUSD6 forming a complex with TMEM127 and MHC-I
Mechanisms of immune evasion in cancer and to recruit WWP2 for lysosomal degradation of MHC-I,
unanswered questions in cancer immunotherapy facilitating immune evasion [231].
The immune system has undergone a transforma- MHC-I, a key factor in immune evasion, undergoes
tive evolution to combat cancer progression. However, internalization and degradation by CEMIP, further
immune responses can be suppressed, and tumor cells reducing immune surveillance [232]. In addition, SOX4-
often employ mechanisms to evade these responses, a induced T cell exhaustion mediated immune evasion.
concept known as immune evasion. Recent studies have The interaction between cancer cells and CD8+ T cells,
shed light on the major mechanisms contributing to the facilitated by Midkine, alters immune system responses
immune evasion of cancer cells. [233]. In PTEN-deficient animal models, PI3Kβ down-
Mutations within tumor cells can facilitate immune regulation results in STAT3 suppression, accelerating
evasion. This is evidenced by the dysregulation of CD8+ immune responses and revealing the potential of PI3Kβ
T cells observed in clinical specimens harvested from in causing immune tolerance and evasion [234].
ovarian cancer patients, accompanied by the activation Chromosomal changes and deletions also play a role in
of immunosuppressive signaling through TGF-β [226]. A immune evasion. Homozygous deletions affecting chro-
well-known mechanism for inducing immune evasion is mosome 9q21.3 impair the function of CDKN2A/B, has-
the upregulation of PD-L1. In hepatocellular carcinoma, tening carcinogenesis. Half of these deletions affect the
USP22 expression increases via PRDM1, leading to IFN gene cluster on chromosome 9q21.3, increasing the
diminished SPI1 degradation through USP22 upregula- escape of tumor cells from CD8+ T cell surveillance [235].
tion. This, in turn, results in increased PD-L1 expression, Maintaining the balance of interferon responses is vital
promoting immune evasion [227]. for cancer immunotherapy, as alterations in interferon
Efforts to suppress PD-L1 have shown promise in and T cell levels can induce immune evasion. mTORC1
disrupting immune evasion. RNF31, with its ability to enhances B7-H3 expression, reducing T cell function and
downregulate PD-L1 by enhancing ubiquitination and IFN-γ responses while increasing MHC-II expression
degradation of YAP, improves the function of CD8+ T [236]. One mechanism causing immune escape involves
reducing the number of T cells, mediated by apoptosis drivers of cancer immunity should be highlighted. More-
induction. Extracellular galectin 4 stimulates T cell apop- over, more investigation should be directed towards
tosis, diminishing immune surveillance. Conversely, the understanding the function of organ-specific tumor
downregulation of galectin 4 promotes M1 polarization immune context. Checkpoint inhibitors are commonly
of macrophages and enhances T cells and dendritic cells, utilized for the treatment of human cancers, but there
disrupting immune escape [237]. is still a long way towards understanding the molecular
The immune cells have shown potential in the identi- landscape of factors regulating primary versus secondary
fication and recognition of neoplastic cells possessing immune escape. There is a big question about whether
initiation mutations to suppress tumorigenesis [238]. it is better to use endogenous or synthetic immunity for
Although the origination of a tumor is from a single the treatment of human cancers. Moreover, since cancer
transformed cell, the presence of genomic instability can immunotherapy has been applied in clinics, there are also
cause the generation of cancer cells that are genetically questions regarding the effective evaluation of cancer
heterogeneous with unique morphological and physi- immunotherapy in clinical studies. One of the hopes is
ological characteristics. Moreover, the tumor cells have the advances in the field of biology highlighting the appli-
shown significant features in terms of surface molecule cation of biomarkers and signatures for cancer immuno-
expression, proliferation and angiogenesis [239] resulting therapy. Therefore, precision medicine can significantly
from the morphological and epigenetic plasticity. Hence, benefit by highlighting the signatures and developing
the cancer cells demonstrate expression of different anti- strategies based on targeting accurate and efficient sig-
gens that may be tumor-specific or tumor-associated, natures for cancer immunotherapy. Another question
differentiation antigens, and lectin-binding sites. Such is that various types of regimens for cancer immuno-
antigens display uneven distribution on tumor subpop- therapy have been developed, and comprehensive stud-
ulations and can stimulate various immune responses ies are required to be performed in improving long-term
[240]. Such tumor heterogeneity can significantly affect survival through a combination of such regimens. In
the genotype, gene expression, cellular morphology, order to optimize the process of cancer immunotherapy,
metabolic activity, motility, and behaviors, including responding to such concerns and questions can improve
proliferation, antigen presentation, drug response, and the potential for the treatment of cancer patients [247].
metabolism [241]. Furthermore, this heterogeneity can be
utilized for the diagnosis, therapeutic efficacy, and recog- Nanoparticles targeting tumor microenvironment
nition of promising targets [242]. Such a heterogeneous components in cancer immunotherapy
nature of cancer cells can provide significant opportu- Nanoparticles targeting tumor-associated macrophages
nities to escape from the function of immune cells. The To address the immunosuppressive role played by
tumor cells significantly proliferate in TME, which can M2-polarized macrophages, the stimulation of M1 polar-
cause hypoxia. The presence of hypoxia in TME recruits ization through nanostructures emerges as a promising
MDSCs and impairs the function of NK cells to provide avenue for enhancing immunotherapy. A pivotal mecha-
a pre-metastatic niche [243], showing that cancer cells nism involves the development of genetically modified
metastasize through suppressing immune surveillance. pristine cells, whose extracted cell membrane is uti-
Upon surgical resection, the cancer cells undergo trauma, lized to coat and functionalize nanoparticles in cancer
and such tumor cells can enhance the generation of cyto- therapy. Biomimetic magnetic nanoparticles featuring
kines and other factors, including IL-6, C-reactive pro- gene-edited cell membranes demonstrate the capacity to
tein (CRP), TNF-α, IL-1β to affect the immune system target multiple pathways, thereby regulating macrophage
[244]. Therefore, the application of conventional thera- polarization and suppressing tumorigenesis. Specifically,
pies and the heterogeneous nature of cancer cells should the presence of gene-edited cell membranes suppresses
be considered in immune evasion. The immune cells are the CD44/SIRPα axis by upregulating SIRPα variants.
able to suppress vulnerable cancer cells presenting tumor Magnetic nanoparticles, forming the core, play a crucial
antigens [245], while the heterogeneous nature of cancer role in re-educating and reprogramming macrophages,
cells allows them to escape such action of the immune thereby accelerating cancer immunotherapy [248].
system. Furthermore, the tumor cells have shown capac- Changes in macrophages extend beyond polarization,
ity to induce apoptosis in tumor-specific cytotoxic T lym- and their role in regulating antigen processing is also
phocytes [246]. significant. Certain clinically important pathways, such
Therefore, since immune evasion commonly occurs as STING, pose a challenge for targeting at the clini-
in cancer, cancer immunotherapy has been introduced. cal level due to a lack of targeted delivery. By function-
Regarding cancer immunotherapy, there are a number of ing as a STING agonist, ZnCDA encapsulates CDA and
challenges that should be addressed. The first and most disrupts the endothelial barrier in cancer vasculature,
important challenge is regarding the fact that dominant facilitating penetration into the TME and tumor site.
These nanoparticles target macrophages, enhancing anti- involves functionalizing them with macrophage mem-
gen processing and expediting T-cell-related responses in branes to enhance efficacy. This hypothesis has been
cancer immunotherapy [249]. A number of nanoparticles tested in experiments, demonstrating the potential of
have shown potential in changing the polarization of membranes derived from tumor-associated macro-
TAMs. In the context of M1 polarization of macrophages, phages with immunomodulatory functions and anti-
different mechanisms are available for the induction of gen-homing affinity. These membranes were employed
polarization of macrophages into the M1 phenotype. to functionalize upconversion nanostructures loaded
Ginseng-derived nanostructures with extracellular vesi- with photosensitizers. Notably, tumor-associated mac-
cle-like properties can stimulate the TLR4/MyD88 axis, rophage membrane-functionalized nanoparticles sup-
resulting in increased M1 polarization of macrophages, press CSF1 and interactions between cancer cells and
elevated ROS levels, and induction of apoptosis in mela- the tumor microenvironment, impairing tumorigenesis.
noma [250]. In fact, the M1 polarization of macrophages Moreover, these nanoparticles stimulate photodynamic
has been accompanied by apoptosis induction. therapy by suppressing the M2 phenotype, enhancing
Although the primary focus of this section is to evalu- M1 macrophage polarization, inducing immunogenic cell
ate the role of nanoparticles in macrophage re-educa- death, and improving the generation of T cells through
tion, studies have demonstrated that membranes can enhanced antigen presentation [254].
be extracted from macrophages to coat and functional- Reorienting macrophages toward the M2 pheno-
ize nanoparticles. This approach results in the develop- type presents a hurdle in achieving successful immu-
ment of biocompatible structures with stealth properties notherapy. This polarization is chiefly instigated by
[251]. Such an approach can be used mutually in which tumor cell-secreted MCSF, resulting in the elevation of
nanoparticles are functionalized with macrophage mem- CSF1-R. Moreover, the heightened expression of SIRPα
brane to improve their targeting ability towards mac- on myeloid cell surfaces activates SHP-1 and SHP-2 in
rophages and TME, and on the other hand, they can macrophages, impeding immunotherapy by hampering
be designed for re-education of macrophages into M1 phagocytosis. Moving beyond macrophage polarization,
phenotype. efforts are redirected to address macrophage activity
Targeting macrophages in cancer treatment is pri- failure. To augment macrophage phagocytosis, promis-
marily driven by their immunosuppressive function. ing strategies involve the regulation of CSF1R and SHP2.
Despite the development of various immune response Nanoparticles laden with CSF1R and SHP2 suppressors
regulation strategies, such as phototherapy-induced induce M1 macrophage polarization, boosting phagocy-
immunotherapy, concerns persist regarding immuno- tosis to impede tumorigenesis [255].
genicity and inflammation induction. Therefore, it is After elucidating the key mechanisms governing mac-
crucial for nanoparticles to employ safe and biocompat- rophage polarization and activity, the subsequent focus
ible mechanisms to counteract macrophage-mediated involves exploring nanoparticles with potential clinical
immunosuppression. The biomimetic Fe3O4-SAS@PLT applications. The FDA-approved ferumoxytol, an iron
nanostructures, derived from sulfasalazine-loaded meso- supplement and iron oxide nanostructure, serves dual
porous magnetic nanostructures and functionalized with roles as a drug delivery system and imaging agent. When
platelets, have been designed to suppress the glutamate- co-cultured with macrophages for treating lung cancer
cystine antiporter system Xc-pathway in ferroptosis metastasis, ferumoxytol upregulates caspase-3, inducing
induction. This ferroptosis induction demonstrates syn- macrophages to express mRNAs for pro-inflammatory
ergistic effects with PD-L1 immune checkpoint immu- Th1-related responses. Ferumoxytol effectively sup-
notherapy, as observed in animal models. Notably, these presses tumor metastasis and proliferation while promot-
biomimetic nanostructures induce ferroptosis, promoting M1 macrophage polarization to enhance the quality
ing M1 polarization of macrophages and disrupting the of cancer immunotherapy [256].
immunosuppressive TME [252]. A growing body of evidence supports the poten-
When considering nanoparticles for modulating mac- tial involvement of tumor-associated macrophages in
rophages, especially for potential use in cancer immu- the development of drug resistance [257, 258]. These
notherapy at the clinical level, biocompatibility is as macrophages play a role beyond immune system regu-
important as functionality. Lipid nanoparticles with cat- lation, influencing the response to chemotherapy. Furin-
ionic features have shown promise as carriers, delivering based aggregated gold nanostructures capitalize on the
mRNA to targeted sites. Loading mRNA for re-educating “enhanced permeability and retention” effect, aggregating
macrophage polarization onto lipid nanoparticles cre- in breast cancer due to furin upregulation. This process
ates safe and biocompatible nanostructures for cancer suppresses exocytosis, leading to increased preferential
immunotherapy [253]. A significant advancement in accumulation at the tumor site. These nanoparticles also
utilizing nanoparticles for macrophage re-education inhibit autophagy, promoting M1 macrophage education
to counteract drug resistance [259]. Table 1 provides a Some nanoparticles are designed to respond to fibro-
concise overview of the applications of nanoparticles in blast activation protein as a CAF biomarker. Albumin
macrophage re-education for cancer immunotherapy. nanostructures encapsulating paclitaxel and functional-
Figure 3 provides an overview of the regulation of tumor- ized with CAP showed promise in targeting fibroblast
associated macrophages by nanoparticles in cancer activation protein in CAFs. Incorporation of the photo-
immunotherapy. sensitive compound IR-780 further enabled near-infra-
red laser irradiation for photothermal therapy, resulting
Nanoparticles targeting cancer-associated fibroblasts in tumor suppression and improved deep tumor pen-
Nanoparticles play a crucial role in influencing cancer- etration [281]. The concept of specifically targeting
associated fibroblasts (CAFs) within the cancer treatment CAFs using their biomarkers has significant potential in
landscape. Interactions between cancer cells and CAFs in enhancing the fight against cancer.
the TME contribute to tumorigenesis, making it essential
to explore nanoparticle applications in suppressing these Nanoparticles targeting T cells
interactions and impeding cancer progression. In ovar- Nanoparticles, through targeted regulation of T cells,
ian cancer, ovarian cancer cells and TME cells promote have emerged as a promising avenue for effective cancer
the activation of ovarian CAFs. Gold nanoparticles with a immunotherapy [282–288]. Increasing the infiltration
size of 20 nm effectively disrupted this interaction, inhib- of CD8+ T cells and T helper cells in the TME is crucial
iting CAF activation and offering potential in the treat- for TME remodeling and activating the immune system
ment of ovarian cancer [275]. against cancer progression. Nanoparticles such as man-
CAFs play a supportive role in tumor metastasis. ganese zinc sulfide nanostructures play a pivotal role in
Core-shell nanoparticles, with gold as the core and sil- mediating this effect [289]. A noteworthy trend in recent
ver as the shell, were effective in suppressing osteopontin years involves the integration of immunotherapy with
expression in CAFs, hindering cancer progression with- other therapeutic modalities like chemotherapy or pho-
out impacting CAF biomarker expression [276]. Besides totherapy. Hybrid prodrug nanocarriers carrying cispla-
modulating CAF activation and secretions, nanostruc- tin and camptothecin, stimulate the cGAS/STING axis
tures may also be used for targeted CAF destruction. and induce DNA damage. Additionally, these prodrug
Ultra-small iron oxide nanocarriers (6 nm in diameter) nanocarriers enhance CD8+ T cell infiltration in the
combined with low-frequency rotating magnetic fields TME, improving immunotherapy outcomes for colorec-
induce mechanical forces, leading to CAF death and tal cancer. These hybrid nanocarriers possess a respon-
lysosomal disruption [277]. Targeting CAFs for destruc- sive feature to reactive oxygen species (ROS) and are
tion enhances nanoparticle internalization. Such a strat- constructed from mPEG2k-DSPE and other polymers
egy addresses the challenge of a dense TME that hinders [290]. The mPEG/PLGA/PLL nanocarriers, delivering
nanoparticle penetration. Ferritin nanocages loaded with CD155-siRNA and modified with PD-L1 antibodies,
the photosensitizer ZnF16Pc and modified with a single- can simultaneously suppress CD155 and PD-L1, avoid-
chain variable fragment that targeted fibroblast activa- ing immune evasion. They enhance CD8+ T cell infiltra-
tion protein, facilitated phototherapy to reduce CAFs tion and induce immunogenic cell death in breast cancer
and improve nanoparticle penetration into the tumor site therapy [291].
[278]. Developing an effective anti-cancer vaccine requires
Nanoparticles can serve dual functions in regulating nanoparticles that can induce systemic immunity.
CAFs and modulating immune responses. Poly(lactic- MnO2-melittin nanostructures, responsive to changes
co-glycolic acid) (PLGA) nanoparticles functionalized in the TME, serve as promising vaccines by trigger-
with cancer cell membrane not only enhanced cancer ing systemic immune responses. These nanostructures
cell-CAF interactions, but also increased antigen uptake, induce cancer cell death through the Fenton reaction in
stimulating CD8+ and CD4+ T cells through MHC-I and the TME, activate the cGAS/STING axis, and enhance
MHC-II, thus promoting cancer immunotherapy [279]. antigen-presenting cell maturation. Furthermore, MnO2-
The fibroblast activation protein, upregulated on CAF melittin nanoparticles stimulate systemic immune reac-
surfaces, represents a promising target in cancer immu- tions, including the promotion of T cells and increased
notherapy. Nanoparticles functionalized with a single- levels of pro-inflammatory cytokines and chemokines
chain variable fragment for ZnF16Pc delivery in cancer [292].
phototherapy lacked systemic toxicity. These function- Combining chemotherapy with phototherapy is
alized nanoparticles suppressed cancer progression in another strategy to expedite tumor suppression. Pro-
both primary and distant sites by accelerating immune drug nanocarriers, developed from hyaluronic acid and
responses and promoting anti-CAF immunity [280]. adamantine-conjugated heterodimers of PPa and JQ1,
target CD44-overexpressed pancreatic cancer cells.
Table 1 Nanoparticle-induced cancer immunotherapy through targeting macrophages
Nanoparticle Cancer type/Cell Size (nm)/Zeta Outcome Refer-
line potential (mV) ence
PEGylated Breast cancer/4T1 75 nm Delivery of mannose and levamisole hydrochloride for glycolysis suppression and reducing mitochondrial energy metabolism [260]
liposomes cells Suppression of cancer proliferation
Pancreatic cancer/ Combination with radiotherapy impairs M2 polarization of macrophages and increases immune responses
murine KPC1245
and KPC1242 cells
Prodrug Colorectal cancer/
39 nm/-8.23 mV Co-delivery of doxorubicin and R848 [261]
nanoparticles MC38 cells 263.2 nm/less than Modification of nanoparticles with bifunctional PD-1/PD-L1 peptide antagonist PCP
Breast cancer/ − 5 mV Cleavage of nanoparticles with FAP-α in the tumor stroma
MCF-7 cells Release of cargo in the tumor site stimulates immunogenic cell death and causes macrophage reprogramming
Lipid Pancreatic cancer/
122.4 nm/+27.82 Loading lipid nanoparticles in injectable hydrogels [262]
Lu et al. Journal of Hematology & Oncology
nanoparticles KPC cells mV Delivery of CCL5-siRNA by lipid nanoparticles to induce M1 polarization of macrophages and enhance T cell-induced immune
responses
Upconversion Breast cancer/4T1 39.5 ± 1.1 and Introduction of upconversion nanoparticles co-doped with perfluorocarbon (PFC)/chlorin e6 (Ce6) [263]
nanostructures cells 54.1 ± 1.3 nm/-19.7 Targeted delivery of paclitaxel as a chemotherapy drug
mV and − 4.1 mV Increasing singlet oxygen production
Stimulating M1 polarization of macrophage in accelerating pro-inflammatory cytokine release to impair breast cancer progression
(2024) 17:16
Iron-chelated Colon and breast 150 nm Stimulating M1 polarization of macrophages and providing photothermal therapy, they accelerated tumor-associated antigen [264]
melanin-like cancers/ CT26 and release to improve cancer immunotherapy
nanocarriers 4T1 cells
Supramolecular Breast cancer/4T1 190.1 nm/-17.1 mV Suppression of CSF1R and MAPK to stimulate M1 polarization of macrophages [265]
nanoparticles cells
MIP-3β plasmid Breast cancer/4T1 90 nm/-2.1 mV Increasing dendritic cell maturation and suppressing M2 polarization of macrophages [266]
cells
Au@PG Lung cancer/ 32.2 nm at 2.5 mM Polyaniline-based glycol-condensation on the nanostructures [267]
nanocarriers Lewis lung carci- ONPG, 29.8 nm at Switching M2 polarized macrophages into M1 polarized macrophages
noma cells 10 mM, 26.4 nm Nanoparticles with smaller sizes demonstrate higher efficacy in the macrophage re-education
at 50 mM, and
18.3 nm at 75 mM
CaCO3-loaded Au Macrophages/ 32 nm Elongating macrophage cell morphology [268]
nanostructures RAW 264.7 cells Stimulation of M1 biomarker and inflammatory cytokines
Inducing M2 polarization of macrophages
Polymeric Osteosarcoma/ 98.4 nm/-14.3 mV Biodegradable nanoparticles for delivery of regorafenib as vascular normalization compound [269]
nanocarriers K7M2 cells Release of cargo upon laser irradiation of 808 nm and increasing hypoxia in TME
Induction of the release of reactive oxygen species and mediation of immunogenic cell death
Stimulation of M1 polarization of macrophages
Gadofullerene Breast cancer/4T1 68.1 nm/-37.7 mV M1 polarization of macrophages and increasing infiltration of T lymphocytes in the TME for cancer suppression [270]
nanocarriers cells
DGL-ZA Breast cancer/4T1 123.1 nm/-13.4 mV Potential cancer biodistribution, extravasation, and high tumor penetration [271]
nanoparticles cells Conjugation of dendrigraft poly-L-lysines as inducers of autophagy
Macrophage regulation and increasing tumor-suppressor activity
Page 13 of 48
This combination of phototherapy and immunotherapy
Refer-
[272]
[273]
[274]
ence
increases T lymphocyte infiltration. Moreover, JQ1 sup-
presses phototherapy-induced immune evasion by down-
Targeted delivery of miR-125b and increasing its transfection more than 6 times to induce M1 polarization and enhance iNOS levels
regulating c-Myc and PD-L1, resulting in significant
tumor suppression [293].
As cancer development is a gradual process, effec-
tive treatment should focus on providing long-term
immunity. The use of cancer vaccines has significantly
increased in recent years; however, a major challenge
remains in the targeted delivery of cargo, including anti-
Externalization of nanostructures occurs when they are exposed to the TME with upregulation of MMP2
gens and adjuvants. To address this issue, glycosylated

poly(lactic-co-glycolic acid) (PLGA) nanocarriers have
been developed for the delivery of the ovalbumin antigen
and CpG as an adjuvant in cancer vaccination. The sur-
face of the nanostructures is modified with galactose or
mannose. These nanoparticles possess high loading abil-
ity and sustained release, which are key features for the
development of cancer vaccines. They stimulate dendritic
cell maturation, promote antigen uptake, and enhance
pMUC1 increases macrophage phagocytosis ability and M1 polarization
CD4+ T cell levels, leading to increased infiltration of

CD8+ T cells in cancer immunotherapy [294].
Increasing depletion of tumular-associated macrophages in TME
An innovative approach in cancer therapy involves

developing nanoparticles that mimic pathogens to induce
a robust immune response. Saccharomyces cerevisiae
Functionalization with mannose and glycocholic acid
(yeast)-based nanocarriers function as nano-patho-

gen-associated molecular patterns (nano-PAMPs) and,
through the induction of Dectin-2 and TLR-4, enhance
Delivery of SIRPα-siRNA and MUC1 pDNA
Increasing immunity by the SIRPα-siRNA
TH17 responses, contributing to anti-cancer immunity

[295]. Stimulation of T helper cells has proven effective
in cancer immunotherapy. Chondroitin sulfate-modified
nanostructures conjugated with glycolic acid or man-
nose, along with cationic liposomes loaded with ovalbu-
Oral delivery of cargo
min, can stimulate the maturation of dendritic cells and

evoke T helper type I and II responses [296]. In many
cases, nanoparticles not only stimulate T cell infiltra-
Outcome
tion, but also accelerate the maturation of dendritic cells,

contributing to cancer immunotherapy [297]. Recogniz-
ing the role of epigenetic changes in immune dysfunc-
tion, the delivery of miRNAs has been explored in cancer
230 nm/at a range
120–160 nm/20
potential (mV)
Size (nm)/Zeta
immunotherapy. Lipid nanoparticles delivering anti-

92 nm/-12 mV
of 20–30 mV
miR-21 have demonstrated the ability to stimulate M1

polarization of macrophages and enhance the infiltration
of CD8+ T cells [298].
mV
Nanoparticles have been employed for targeted regu-

Melanoma/B16F10
Breast cancer/4T1
Cancer type/Cell
lation of immunosuppressive Treg cells in cancer treat-

Non-small cell
ment, aiming to enhance immunotherapy potential. For

lung cancer
example, PLGA nanoparticles with antigen-capturing

capabilities have been developed for this purpose. These
cells
cells
Table 1 (continued)
line
nanoparticles primarily elevate the CD8+ T cell count,

consequently increasing the ratio of cytotoxic T cells to
san nanoparticles
Hyaluronic acid-
serine-modified
Trimethyl chito-
Treg cells [299]. By augmenting this ratio, the negative

functionalized
Nanoparticle
Phosphatidyl-
nanoparticles
nanoparticles
impact of Treg cells on immune responses can be allevi-

ated. For enhanced cargo delivery, layer-by-layer nano-
structures, composed of GITR/PLGA and modified with
Fig. 3 The impact of nanoparticles on macrophages, showcasing their potential to re-educate and impede cancer progression. These nanoparticles
effectively target key mechanisms associated with the M2 polarization of tumor-associated macrophages. They inhibit CD44/SIRPα, CS1R, and MAPK,
prompting the M1 polarization of macrophages. Additionally, nanocarriers activate the TLR4/MyD88 axis, contributing to increased M1 polarization of
the tumor-associated macrophages. The nanoparticles further induce ferroptosis and photodynamic therapy, disrupting the polarization of these macro-
phages into the M2 phenotype (Created by Biorender.com)
PLG and PLH that are responsive to the TME pH, have cancer immunotherapy, has shown promise in re-educat-
been designed to deliver IR780 dye. Subsequent irradia- ing the TME and enhancing macrophage phagocytosis
tion with a 808 nm laser promotes the maturation of den- activity. Co-assembled prodrug nanoparticles, designed
dritic cells, thereby increasing the activity of CD8+ and with hyaluronic acid-cisplatin/polystyrene-polymetfor-
CD4+ T cells in cancer immunotherapy. Notably, these min, effectively co-deliver metformin and cisplatin. With
nanoparticles exhibit a suppressive effect on Treg cell a size of 166.5 nm and a zeta potential of -17.4 mV, these
function, contributing positively to immune reactions nanoparticles exhibit high potential in cancer immuno-
[300]. therapy. They induce apoptosis through PARP upregula-
Several widely used chemotherapeutic drugs, includ- tion, enhance cisplatin sensitivity by suppressing ERCC1,
ing doxorubicin, face limitations such as low tumor site and modulate AMPKα/mTOR pathways to increase
accumulation and the development of drug resistance. CD8+ and CD4+ T cells, and reduce Treg cell numbers
Prodrug nanocarriers based on doxorubicin and indoxi- [302].
mod have been developed to suppress the IDO pathway. Unmodified nanoparticles exhibit poor specific target-
These prodrug nanocarriers induce immunogenic cell ing of Treg cells. This prompted the use of nanocarrier
death, enhance the infiltration of cytotoxic T cells (CD8+ functionalization. Hybrid nanocarriers functionalized
T cells), and suppress Treg cells, MDSCs, and TAMs in with tLyp1 peptide have been developed to suppress
the TME, thereby effectively promoting T cell/Treg cell STAT3 and STAT5, reducing Treg cell numbers and
ratio for cancer immunotherapy [301]. increasing the infiltration of CD8+ T cells in the TME
Co-delivery strategies have been used to improve can- [303]. The functionalized nanoparticles contribute
cer immunotherapy. Metformin, a compound utilized for to tumor suppression by increasing the infiltration of
dendritic cells, CD8+ T, and natural killer cells, while to increase ROS generation, mediating immunogenic
reducing Treg and MDSC cells [304]. Furthermore, poly- cell death (ICD) for cancer immunotherapy. Moreover,
merosomes have been shown to stimulate the STING these nanoparticles reprogram macrophages from M2 to
axis and enhance the infiltration and proliferation of T M1 [269]. In another effort, albumin-based nanostruc-
cells in cancer immunotherapy [57]. Table 2 summarizes tures have been developed for the co-delivery of IR780,
the application of nanoparticles for the regulation of T NLG919, and hypoxia-activated prodrug tirapazamine
cells in cancer therapy. Figure 4 demonstrates the role of (TPZ) in synergistic tumor suppression. Exposure to
nanoparticles in the regulation of CAFs, T cells, and Treg nanoparticles to NIR irradiation mediates the generation
cells. of 1O2 to trigger the release of ROS-responsive linker for
TPZ release, causing chemotherapy through enhancing
Nanoparticles regulating hypoxia tumor hypoxia. Moreover, these nanostructures stimu-
In each tumor, the levels of oxygen are different [318]. late ICD to enhance the activity of cytotoxicity of T lym-
The oxygen insufficiency in tumor tissue generally ranges phocytes [333]. Doping the nanoparticles with Mn2+ can
from more or less anoxic state (almost no oxygen) to alleviate hypoxia and increase cGAS sensitivity, inducing
60 mm Hg (8% oxygen). In spite of this, the tumor cells the cGAS/STING pathway, causing macrophage re-edu-
demonstrate a specific condition known as hypoxia in cation, and increasing the maturation of dendritic cells
which oxygen levels fluctuate from anoxia to 7.5 mm Hg [334]. In a number of cases, the hypoxia is boosted in the
(about 1% oxygen) [319]. Hypoxia can be considered a TME to promote the release of drugs from nanoparticles
reliable biomarker, since it promotes the progression of for cancer immunotherapy [335]. Furthermore, mac-
tumor cells and can cause therapy resistance [320]. Along rophage-mimetic microalgae and liposomes have been
with tumorigenesis, the hypoxia in cancer enhances, and conjugated to suppress autophagy and reduce hypoxia in
it shows some coordination with angiogenesis, prolifera- cancer immunotherapy [336]. Regarding autophagy regu-
tion, and metastasis. Hypoxia is able to enhance the lev- lation, it should be highlighted that autophagy has a dual
els of CCL22, CCL28 and increases the accumulation of function in cancer and can exert carcinogenic and anti-
MDSCs and Tregs to mediate immunosuppressive TME carcinogenic functions, complicating its regulation in
[321–323]. Furthermore, hypoxia has been shown to be cancer therapy [337, 338]. According to these studies, the
a factor involved in immune resistance [324]. Metformin regulation of hypoxia by nanoparticles can pave the new
is able to improve cancer immunotherapy by impairing gate for cancer immunotherapy [339–342].
the function of hypoxia in impairing CD8+ T cells [325].
Exercise has been shown as a mechanism for apoptosis Nanoparticles targeting myeloid-derived suppressor cells
induction and decreasing the proliferation of cancer cells. The infiltration of MDSCs is against anti-cancer immu-
Moreover, exercise can ameliorate hypoxia, and enhance nity since it impairs T-cell proliferation and enhances the
the function of T cells and reduces levels of Treg cells differentiation of Treg cells [343]. MDSCs are consid-
in cancer immunotherapy [326]. Hypoxia has been also eredimmature myeloid cells with a heterogeneous nature
shown as a mechanism in increasing M2 polarization of providing, an immunosuppressive TME [172]. Over-
macrophages and secretion of factors with immunosup- all, MDSCs utilize three distinct mechanisms to cause
pressive function, including VEGF and TGF-β. Moreover, immunosuppression. In the first method, the arginase
hypoxia has been suggested to cause therapy resistance, 1 and iNOS undergo upregulation in MDSCs, and they
especially during photodynamic therapy and radiation in can deplete L-arginine which is vital for the proliferation
which oxygen molecules are required for cancer suppres- of T cells and CD3 ζ-chain formation of TCR. However,
sion [180, 327, 328]. enhancement in arginase 1 activity and iNOS can sup-
Therefore, the function of hypoxia in cancer immuno- press the proliferation and function of T cells [344–347].
therapy is of importance [329]. Hypoxia can be exploited In the second method, the MDSCs can enhance the gen-
by the nanoparticles for improving their specificity and eration of ROS and RNS to mediate dysfunction in T
recently, the hypoxia-responsive nanostructures have cells [348–350]. The ROS and peroxynitrite derived from
been designed for cancer immunotherapy [330–332]. MDSCs can cause post-transcriptional alterations in
However, most of the attention has been paid to the TCR and CD8 to interfere with the function of periph-
regulation of hypoxia in cancer immunotherapy. The eral CD8+ T cells and cause antigen-specific tolerance in
biodegradable NIR-II pseudo conjugate polymeric nano- these cells through impairing binding affinity to phos-
structures can regulate hypoxia in cancer immunother- phorylated MHC molecules [348]. In the third and final
apy. These nanostructures can deliver regorafenib and way, MDSCs are able to enhance Treg cell differentiation
respond to 808 nm laser irradiation to release drugs for to disrupt anti-cancer immunity [172, 351]. Upon that,
the reduction of cancer hypoxia through vascular nor- Treg cells secrete a number of inhibitory cytokines such
malization, allowing for oxygen entrance into tumors as IL-10, IL-35, and TGF-β to interfere with the proper
Table 2 Nanoparticle-mediated T cell regulation in cancer therapy
Nanoparticle Cancer type/Cell line Size (nm)/Zeta potential Highlights Refer-
(mV) ence
Polymeric Lung cancer/LLC cells 75.9 ± 0.98 nm/32.5 ± 1.5 ROS-responsive nanocarriers for the co-delivery of FGL1- and PD-L1-siRNA [305]
nanoparticles mv Development of nanoparticles from poly-l-lysine-thioketal and modified cis-aconitate to facilitate endosomal escape
Functionalization of nanoparticles with iRGD peptide
Enhancing infiltration of CD4+ and CD8+ T cells in cancer immunotherapy
Chiral Lymphoma/EG7.OVA - Stimulation of NK and CD8+ T cells [306]
nanoparticles cells
Biomimetic Colon cancer/CT26 - The phospholipid nanoparticles (PL1) can provide targeted delivery of mRNA (CD137 or OX40) in the stimulation of T [307]
nanoparticles cells cells
Cisplatin Lung cancer/LLC 14.4 ± 3.3 nm/-12.8 mV Enhancing CD8+ T cell priming through elevating antigen presentation and providing T cell crosstalk [308]
nanoparticles
Lipid Colon cancer/MC38 - Stimulation of CD8+ T cells and reprogramming TME to disrupt the proliferation of cancer cells [309]
nanoparticles cells
Endogenous Breast cancer/4T1 cells −15 ± 3.3 mV Increasing proliferation of CD4+ and CD8+ T cells and promoting the ratio of cytotoxic T cells compared to Treg cells [310]
antigen-carrying
nanoparticles
Cationic polymer- Melanoma/B16F10 163.9 ± 0.61 nm, Development of nanocarriers based on polyadmidoamine dendrimers and poly(d,l-lactic-co-glycolic acid) [311]
(2024) 17:16
ic nanostructures cells 523.9 ± 15 nm and Development of cancer vaccine

1278.3 ± 27 nm/less than Enhancing the number of T cells in the peripheral blood
60 mV
Platelet Breast cancer/4T1 cells −38.0 ± 0.4 mV Co-delivery of anti-PD-L1 antibodies and iron oxide nanoparticles as photothermal agents in cancer therapy [312]
Stimulation of necrosis through phototherapy
Stimulation of innate immune responses
Promoting infiltration of CD4+ and CD8+ T cells
Bacterial mem- Melanoma/B78 cells 207 nm/-11 mV Comprised of PC7A/CpG core with immune system induction ability [313]
brane-coated The presence of bacterial membrane and imide groups can increase antigen retrieval
nanoparticles Capturing neoantigens and their presentation to dendritic cells
Stimulation of T cell responses
Photo-respon- Colon cancer/CT26 88.1–119.2 nm Delivery of VPF as photosensitizer, FRRG and doxorubicin [314]
sive prodrug cells Stimulation of immunogenic cell death
nanoparticles ERP effect
Maturation of dendritic cells for cross-presenting of antigens to T cells
K3ZrF7:Yb/Er Breast cancer/4T1 cells 20 nm Increasing ROS levels [315]
upconversion Capase-1 upregulation
nanocarriers Gasdermin D cleavage
IL-1β maturity
Cytolysis induction
Increasing dendritic cell maturation and promoting number of effector-memory T cells
Prodrug Colon cancer/CT26 70 nm/-17 mV Targeted delivery of camptothecin and assembling with PEGylated lipids [316]
nanoparticles cells Increasing half-life and blood circulation
Enhancing infiltration of CD8+ T cells
Page 17 of 48
function of the immune system [352, 353]. Therefore, tar-
Refer-
[317]
ence
geting MDSCs is critically vital for anti-cancer immunity.
The intravenous administration of DNA thioaptamer-
functionalized liposomes can cause specific targeting of
TME, particularly MDSCs. Moreover, such liposomes
provided targeted delivery of doxorubicin in breast can-
cer animal models to enhance infiltration of CD8+ T cells
and diminish MDSCs [354]. Notably, there are different
kinds of immune response-related molecules in TME,
including IL-1β [355, 356], IL-6 [357], prostaglandin E2
[358], VEGF [359], and IFN-γ [351] that disrupt the dif-
ferentiation procedure to increase the accumulation
of immature myeloid cells [360]. As a result, one of the
promising strategies can be targeting MDSCs for mediat-
ing their differentiation into other kinds of immune cells.
In line with this, the lipid-coated biodegradable hollow
mesoporous silica nanostructures have been introduced
to regulate MDSC differentiation. Such nanostructures
are able to co-deliver IL-2 and all-trans retinoic acid to
trigger the MDSC differentiation into mature dendritic
cells, macrophages and granulocytes. These nanoparti-
cles showed significant capacity in enhancing the number
Polarization of macrophages into M1 phenotype
of mature dendritic cells and decreasing MDSCs. Fur-

thermore, these nanoparticles stimulated CD4+ and CD8+
T cells and increased the secretion of IL-12 and TNF-α as
Acceleration of immunosuppression
anti-tumor cytokines [361].
Nanoparticles for delivery of cargo into antigen-presenting

cells and lymph nodes
Increasing CD8+ T cells
Apoptosis induction
One of the prominent problems in cancer eradication

using immunotherapy is the lack of effective and proper
delivery into APCs and lymph nodes. The nanoparticles
Highlights
have opened a new gate for the delivery of immuno-

therapeutics into APCs and lymph nodes [362]. Note-
worthy, a number of nanostructures based on their
design, demonstrate the immunostimulatory impact,
Cancer type/Cell line Size (nm)/Zeta potential
and even in lack of delivery of cargo, they can stimulate

T and B cell responses [363, 364]. The tumor antigens
have been conjugated into nanostructures, and upon
30 nm/-20 mV
injection into OVA-expressing melanoma, thymoma, or

lymphoma-bearing mice, they caused significant anti-
(mV)
cancer immunity [365, 366]. Furthermore, such model

antigens conjugated into nanostructures triggered T
cell and antibody responses against lymphoma or colon
Melanoma/B16F10
tumors to impair cancer growth and enhance the sur-

vival of animal models [366–368]. The particle size has
been considered an important factor in this case, as small
virus-size particles (≤ 40 nm) can reach the lymph nodes
cells
Table 2 (continued)
and demonstrate high cellular uptake by dendritic cells.

Then, the peptide presentation from coated antigen by
Lipid-coated cal-
cium phosphate
dendritic cell-related MHC class I molecules occurs and

Nanoparticle
nanoparticles
the stimulation of CD8+ T cells is observed [369, 370].

The endocytosis of such nanostructures by dendritic cells
can stimulate the danger-sensing pathway in dendritic
Fig. 4 Nanoparticles orchestrating immune cells and cancer-associated fibroblasts (CAFs). Nanoparticles elevate antigen presentation via MHC-I and
MHC-II, stimulating CD4+ and CD8+ T cells, thereby facilitating cancer immunotherapy. The nanostructures amplify Dectin-2 and TLR-4 levels, fostering
TH17 responses for effective cancer immunotherapy. Additionally, they boost dendritic cell maturation and, through the delivery of anti-miR-21, induce
polarization of macrophages into the M1 phenotype. The nanoparticles’ downregulation of osteopontin in CAFs disrupts cancer progression. Moreover,
these nanoparticles suppress Treg cells, preventing immunosuppression (Created by Biorender.com)
cells and mature them for immunogenic APCs [371]. can reach the tumor tissues, lacking clinical importance
The tumor antigen should reach the tumor-draining and therapeutic value in the clinical setting [384]. There-
lymph nodes to be absorbed by professional APC cells fore, significant efforts have been made to improve the
such as dendritic cells, and then, their presentation to T ability of nanoparticles to reach tumor tissues and opti-
cells occurs. The tumor-specific T cells have been found mize the nanostructures in a way to control biologi-
in lymph nodes. However, the dendritic cells in tumor- cal interactions due to the complicated nature of TME
draining lymph nodes demonstrate an immature/inactive resulting from irregular vascular distribution, high tumor
form that compromises their ability to induce anti-tumor interstitial fluid pressure, low blood flow, dense EZN
T cell responses [372–379]. The nanoparticle-bound and high number of stroma cells. Therefore, the strate-
cytosine-phosphate-guanine (CpG) oligonucleotides gies should be directed towards enhancing the entry of
(an adjuvant) have been shown to accumulate in tumor- nanostructures into tumor tissue that can be obtained
draining lymph nodes in melanoma to induce dendritic through improving tumor perfusion, elevating tumor
cells [380]. vasculature permeability, and mediating ECM remodel-
ing. As an example, the nanostructures applied for ECM
Nanoparticles targeting tumor cells degradation or restoring tumor vasculature into normal
A high number of nanostructure-based methods need condition [385] can mediate TME priming to provide
tumor infiltration by nanoparticles [381]. The clinical desirable immune reactions, reversing immunosuppres-
implication of EPR [382, 383] is still under question and sive TME and enhancing anti-cancer immunity [386].
a controversial debate, and there is a discussion in which In cases where tumors are accessible, the intratumoral
only a small proportion of administered nanostructures administration of nanoparticles is preferred into systemic
injection to enhance accumulation at the tumor region. improve the potential PD-L1 blockade in cancer immu-
The proper accumulation of nanoparticles in TME and notherapy [404]. For stimulation of ICD, various kinds of
the release of therapeutic cargo can enhance tumor sup- nanoparticles including polymeric nanostructures [405,
pression, while it reduces the adverse impacts. A number 406], liposome-modified polysopamine structures [407],
of clinical studies have suggested the intratumoral injec- cRGD-functionalized TPGS nanoparticles [408], iron
tion of immunotherapeutic compounds [387, 388] which (II)-cytosine-phosphate-guanine nanoparticles [297] and
has also been confirmed in pre-clinical studies upon iron oxide nanostructures [409] have been introduced to
intratumoral injection of immune checkpoint inhibitors enhance cancer immunotherapy. Therefore, nanoparti-
[389]. The nanoparticles optimized to bind into ECM or cle-mediated ICD can cause stimulation of dendritic cells
cancer cells can enhance the accumulation of these struc- to activate T cells in lymph nodes for increasing cancer
tures in the tumor region [390] and provide a new insight immunotherapy.
into the effective delivery of therapeutics into tumor cells
or TME. Cell membrane-coated biomimetic nanostructures
Cancer cell membrane-functionalized nanoparticles
Nanoparticles in immunogenic cell death: a Biomimetic nanoparticles are characterized by struc-
rational way in cancer immunotherapy tures whose surfaces are modified or coated with mem-
In recent years, ICD has been considered a promis- branes from other cells. The development of biomimetic
ing strategy in cancer therapy [391]. The stressed and nanoparticles aims to enhance stealth properties, pre-
dying cells release damage-associated molecular pat- venting their identification by the reticuloendothelial
terns (DAMPs) to mediate innate anti-cancer immune system. Biomimetic nanoparticles exhibit good biocom-
response and increase T lymphocyte-induced tumor patibility, making them widely applicable in cancer treat-
immunity [392]. The ICD is capable of mediating T cell- ment. Recent studies have explored the potential of
induced anti-cancer immune responses against tumor biomimetic nanoparticles in cancer therapy, demonstrat-
antigens [393]. In recent years, the stimulation of ICD by ing their versatility when modified with aptamers [410],
nanoparticles has been suggested as a promising strategy facilitating chemotherapy through co-delivery of chemo-
in cancer immunotherapy. The PLGA nanostructures therapy drugs and natural products [411], and showcas-
have been loaded with potassium chloride nanoparticles ing high penetration and targeting features [412]. They
and then, functionalized with the cancer cell membrane have also been utilized for bioimaging and immunother-
to release K+ and CI− ions upon lysosomal degradation. apy [413, 414], evading the mononuclear phagocyte sys-
Then, these ions cause cancer cell death by mediating a tem [415] and improving blood circulation time [416].
hypertonic state in which cells secrete adenosine triphos- The application of biomimetic nanoparticles in cancer
phate (ATP) and high mobility group box 1 (HMGB-1) immunotherapy has shown promising results in tumor
for stimulation of ICD [394]. The β-D-Glucose-reduced suppression. In some cases, chemotherapy using bio-
silver nanostructures can release calreticulin and increase mimetic nanoparticles can activate the immune system.
the release of HSP70, HSP90, HMGGB1, and ATP [395]. For instance, cancer cell membrane-functionalized phos-
These factors are prerequisites for the induction of ICD. phorus dendrimer-copper(II) complexes (1G3-Cu) and
In a novel strategy, the chitosan-coated PLGA nanopar- toyocamycin (Toy)-loaded polymeric nanocarriers with a
ticles have been loaded with HPV16 E744 − 62 peptides and size of 210 nm can be cleaved in the TME to release cargo
then, their functionalization with ICD tumor cell mem- and reduce glutathione levels. By causing mitochondrial
brane has been performed to enhance the maturation dysfunction and endoplasmic reticulum stress, these
of dendritic cells for cancer immunotherapy [396]. Fur- nanocarriers trigger apoptosis and immunogenic cell
thermore, the Fe3O4 nanostructures have been modified death. They accelerate the maturation of dendritic cells
with living bacteria and cancer cell membranes to cause and increase T lymphocyte infiltration. With the applica-
ferroptosis and ICD for enhancing anti-cancer immune tion of PD-L1 antibodies, the nanoparticles can enhance
responses [397]. Therefore, the increasing evidence high- chemotherapy, impair relapse, and prevent the invasion
light the application of nanostructures for the stimula- of cancer [417].
tion of ICD in cancer immunotherapy [304, 398–403]. Biomimetic nanoparticles also serve as effective car-
In an effort, albumin nanostructures have been devel- riers for delivering siRNA. Recognizing PD-L1 as an
oped in which IR780, as photosensitizer was loaded in immune evasion factor, its downregulation by siRNA
core and cGAS-STING agonists/H2S producer-ZnS was can expedite cancer immunotherapy and prevent T cell
loaded in shell to mediate photodynamic and photother- exhaustion [418]. These nanoparticles exhibit the capa-
mal therapy. These nanostructures mediated pyroptosis bility to effectively suppress cancer progression in vivo,
through the caspase-3/GSDME axis in mediating den- making them promising candidates for the development
dritic cell maturation. Then, T cells are activated and of cancer vaccines [419].
The field of cancer therapy has undergone a revolu- blood cells may also be utilized for the development of
tionary transformation with the application of nanogels biomimetic nanocarriers [429, 430].
as drug carriers [420, 421]. Nanogels exhibit favorable One of the main reasons for the modification of
physicochemical features. They are potential carriers for nanoparticles with the cancer cell membrane is to pro-
delivering both hydrophobic and hydrophilic drugs [422], vide an antigen resource [431, 432]. The PLGA structures
recombinant proteins [423], and genetic materials [424]. have been functionalized with the membrane of mela-
Nanogel-induced immunotherapy has proven effec- noma cells and then, monophosphoryl lipid A (MPLA) as
tive in impeding cancer progression. Polymeric an adjuvant was embedded into nanoparticles to stimu-
nanogels, developed from PDEA-co-HP-β-cyclodextrin- late the maturation of dendritic cells for enhancing anti-
co-Pluronic F127 and a charge-reversible polymer named gen-specific T cell response [433]. Since the expression
dimethylmaleic anhydride-modified polyethyleneimine, of MHC-I can be found in all cells, such as tumor cells,
undergo degradation in the TME. These nanogels, func- the cancer cell membrane-functionalized nanostructures
tionalized with cancer cell membranes, co-deliver pacli- can be considered novel APC to induce T cells, even in
taxel and IL-2, inducing the maturation of dendritic cells the absence of professional APCs. The CD80-expressing
and enhancing the infiltration of effector cells [425]. cancer cells were utilized to derive cell membranes for
Stimuli-responsive biomimetic nanocarriers have coating nanoparticles. These nanostructures can directly
been engineered to optimize cancer immunotherapy. induce antigen-specific T cells through the interac-
Polydopamine-CaCO3 nanocarriers, functionalized with tion of CD28 with cognate T cell receptors, suppressing
cancer cell membranes and featuring pH-responsive tumorigenesis in prophylactic and therapeutic tumor
characteristics, enable phototherapy and bioimaging. models [288]. Furthermore, the cancer cell-membrane
Exposure to the TME triggers the degradation of nano- functionalized nanoparticles could be considered as vac-
carriers, releasing CO2 bubbles that promote photo- cines. Despite significant efforts to highlight the potential
therapy-mediated immunotherapy. Combining this with of cancer cell membrane-functionalized nanoparticles
checkpoint inhibitors further enhances tumor immuno- in cancer immunotherapy, there are several limitations
therapy [426]. to be considered for future studies. Recent studies have
In the realm of biomimetic nanovaccines, studies have highlighted the potential of ferroptosis in cancer immu-
primarily focused on delivering therapeutics or stimu- notherapy [434–436]. More effort regarding the applica-
lators to dendritic cells. However, the presence of the tion of biomimetic nanoplatforms in the regulation of
endocytosis system and endosomal degradation can hin- ferroptosis and related pathways should be performed to
der the effectiveness of these nanovaccines. To address facilitate cancer immunotherapy. Moreover, autophagy is
this issue, biomimetic nanoplatforms have been devel- another factor in the regulation of cancer immunother-
oped to accelerate the internalization of nanoparticles in apy [437–440]. The biomimetic nanoparticles should be
dendritic cells. Utilizing ROS-responsive nanoparticu- designed in a rational way to modulate autophagy for the
late cores fused with peptides and cell membranes, these regulation of T cells and other components of immune
nanovaccines induce micropinocytosis, facilitating direct systems as well as reprogramming macrophages for effec-
cytosolic delivery of Stimulator of Interferon Genes tive cancer immunotherapy.
(STING) agonists. This enhances dendritic cell matura-
tion and T cell priming through STING upregulation in Red blood cell-functionalized nanoparticles
cancer immunotherapy [427]. Red blood cells (RBCs) have obtained much attention for
The stimulation of immunogenic cell death and the the purpose of drug delivery due to a number of char-
promotion of dendritic cell maturation and T cell infil- acteristics, including biocompatibility, biodegradabil-
tration represents the primary strategy utilized by biomi- ity, long lifespan, and desirable encapsulation capacity
metic nanocarriers in cancer immunotherapy. Regulation [441]. The OVA-encapsulated RBCs are able to stimu-
of metabolites is crucial for achieving better immuno- late CD4+ and CD8+ T cells after intravenous injection in
therapy responses and immunogenic cell death. Zinc mice [442]. There is also a promising approach in which
ions-bonded ZIF-8 frameworks with CuS nanodots, RBC membrane is utilized to coat the nanostructures for
functionalized with cancer cell membranes, have been the development of vaccines with long circulation abil-
introduced to amplify photothermal-mediated immu- ity [443]. In an attempt, RBC membrane-functionalized
notherapy through Zn2+ metabolic modulation. These PLGA nanoparticles were designed to deliver both anti-
frameworks induce immunogenic cell death, enhance gen hgp10025 − 33 and adjuvant MPLA. In order to selec-
dendritic cell maturation, and increase T cell infiltration tively target the dendritic cells, mannose was included in
[428]. Although less explored compared to macrophage- the RBC membrane, and these structures demonstrated
and cancer-derived membranes, the membranes of red high potential in suppression of melanoma [444]. How-
ever, the studies are limited, and more experiments
regarding the application of other kinds of nanostruc- nanostructures with macrophage membranes has been
tures, such as metal and carbon nanomaterials, and their performed to increase their escape from phagocytosis
modification with RBC membrane should be performed and improve the potential in cancer therapy [452]. In
to improve the potential in cancer therapy. addition to high specificity in tumor targeting, the mac-
rophage membrane-functionalized nanoparticles dem-
Platelet-functionalized nanoparticles onstrate high biocompatibility that, along with their
Platelets are released by megakaryocytes, and they can anti-cancer activity, are promising candidates for tumor
control homeostasis, tumor invasion, and overall physi- eradication [251, 453]. Therefore, increasing evidences
ological and pathological events. Since the platelets have highlight the application of macrophage membrane-func-
shown expression of self-recognized proteins, includ- tionalized nanoparticles in cancer therapy [454–459]. In
ing CD47, they are beneficial for reducing clearance and order to better highlight their potential, it is suggested
stimulation of the complement system to enhance the to develop biomimetic nanoparticles functionalized with
blood circulation time of nanostructures [445, 446]. The cancer and macrophage membranes to improve potential
platelet membrane-functionalized nanoparticles have in cancer immunotherapy.
been exploited to deliver R848 as a TLR7/8 agonist in The biomimetic nanoplatforms are also interesting for
enhancing accumulation at the tumor region and pro- the regulation of specific mechanisms such as hypoxia
moting the interaction with TME components. More- and lipid metabolism in TME. Biomimetic nanoparticles
over, even at low doses (18 µg vaccine per mouse), they may be designed to present tumor antigens and co-stimu-
could suppress tumors in 87.5% of mice [447]. More- latory molecules simultaneously for cancer immunother-
over, there is the possibility of embedding metformin apy [460]. The most effective strategy thus far is centered
and IR780 as photosensitizers in platelet membranes around the development of biomimetic nanoparticles
to stimulate ICD and improve the potential in cancer with pathogen-like features. These biomimetic nanopar-
immunotherapy through suppressing MDSCs and Treg ticles can elicit significant and long-term immune
cells [448]. However, the potential of these nanocarriers responses in cancer therapy. One of the key reasons for
in the regulation of TAMs and CAFs for cancer immuno- the application of biomimetic nanoparticles is their abil-
therapy should be highlighted. ity to enhance the blood circulation time of cargo. Cho-
lesterol reduction in the membrane used for nanoparticle
Macrophage membrane-functionalized nanoparticles functionalization improves blood circulation time and its
The advantage of pH-sensitive biomimetic nanoparticles effectiveness in inducing cancer immunotherapy [461].
lies in their ability to induce cancer immunotherapy in a Because of rapid cancer cell proliferation, the hypoxic
more specific manner due to targeted decomposition in and nutrient-deficient conditions within the TME hin-
the TME. Immunotherapy with the use of biomimetic der the proper functioning of immune cells. The devel-
nanocarriers may be enhanced through phototherapy. opment of a biomimetic platform to increase glucose
Photo-responsive nanocarriers, through the accel- and glutamine levels required by T cells can reprogram
eration of ROS generation, mediate immunotherapy. the TME, and accelerate cancer immunotherapy [462].
Macrophage membrane-based vesicles, functioning Table 3; Fig. 5 summarize the application of biomimetic
as nanoparticles, deliver drugs and photosensitizers nanoparticles in cancer immunotherapy.
(TAPP) to induce pyroptosis. These biomimetic vesicles,
releasing copper ions, mediate ROS-induced pyropto- Exosomes as emerging nanostructures for cancer
sis. Utilized as nanoparticles, they increase ROS levels, immunotherapy
inducing pyroptosis through the upregulation of caspase- Exosomes, ranging in diameter from 30 to 150 nm, are
3-induced gasdermin E, resulting in pyroptosis-induced extracellular vesicles secreted by eukaryotic cells [470].
immunotherapy [449]. They play a crucial role in intercellular communication
The macrophage membrane-functionalized nano- by carrying lipids, proteins, and nucleic acids. After their
structures have shown high potential in specific tumor secretion into the extracellular matrix, exosomes can be
targeting [450]. The macrophage membrane-coated found in various biological fluids such as amniotic fluid,
nanoparticles have been utilized for the delivery of saliva, urine, and breast milk, among others [471, 472].
saikopsaponin D, and the surface has been hybridized In recent years, there has been a significant increase in
by adding T7 peptide to provide macrophage-homing the application of exosomes in the field of cancer therapy,
capacity for nanostructures and target the tumor cells with a heightened focus on the diverse cargo they can
upregulating transferrin receptor. These nanoparticles transport. Exosomes exhibit the ability to target various
specifically accumulate at the tumor site and can escape cell types within the body and serve as reliable biomark-
phagocytosis by the reticuloendothelial system [451]. The ers for cancer. Advancements in bioengineering tech-
functionalization of MOF-derived mesoporous carbon niques have enabled the effective delivery of cargo using
Table 3 Application of biomimetic nanostructures for enhancement of cancer immunotherapy
Vehicle Cancer type/ Size (nm)/zeta Highlights Ref-
Cell line potential (mV) er-
ence
Biomimetic Breast 500 nm Loading 5-aminolevulinate hydrochloride (HAL) and 3-methyladenine (3MA) into cancer cell-derived microparticles
nanovesicles cancer/4T1 Increasing biosynthesis of PpIX in mitochondria, causing ROS generation after irradiation and increasing mitochondrial dysfunction [463]
cells Suppression of mitophagy

PD-L1 downregulation to mediate immunogenic cell death
Hybrid Breast 180 nm/−18.93 mV Development of hybrid nanoparticles from GTe and modification with cancer cell membrane and bacterial outer membrane
nanoparticles cancer/4T1 and − 26.4 mV GTe functions as a radiosensitizer and the membranes can increase anti-cancer immune responses [464]
cells Increasing ROS generation
Stimulation of immunogenic cell death
(2024) 17:16
Biomimetic - - Functionalization of nanoparticles with cancer cell membrane

nanovaccine Co-delivery of CpG and propranolol [465]
High accumulation in lymph nodes and enough drug release
Increasing dendritic cell maturation and antigen presentation
Enhancing CD8+ T cell priming and
Promoting infiltration of B and NK cells
Inhibiting the immunosuppressive TME
Biomimetic PLGA 147.8 nm/-1.8 mV Delivery of 2-bromo-palmitate by PLGA nanoparticles to increase its potential in breast cancer therapy
nanoparticles Functionalization of nanoparticles with cancer cell membrane [466]
Downregulation of PD-1/PD-L1
Porous silicon@Au Breast Up to 243.30 nm Functionalization of nanocomposites with cancer cell membrane
nanocarriers cancer/4T1 Stimulation of anti-cancer immune responses and relieving immunosuppressive microenvironment [467]
cells Suppressing the proliferation and invasion of cancers
AIEgens Breast 113.2 nm/-12.8 mV Modification with dendritic cell-derived membrane
cancer/4T1 Accumulation in lipid droplets of cancer cells [468]
cells The presence of cell membrane allows to accelerate hitchhiking of AIEdots into T cells and stimulates them in cancer immunotherapy
FePSe3 nanosheets Colon cancer/ + 28.5, + 24.0, + 37.8, Modification of nanoparticles with cancer cell membrane
CT26 cells and + 0.2 mV Loading anti-PD-1 peptide in the nanoparticles [469]
Phototherapy-induced immune responses and tumor ablation
Suppression of PD-1/PD-L1 axis to stimulate T cells
Page 23 of 48
Fig. 5 Biomimetic nanoparticles may be developed by the extraction of membranes from red blood cells, cancer cells, TAMs and CAFs. These modifica-
tions improve the potential of nanoparticles in cancer immunotherapy. Biomimetic nanoparticles may be utilized for drug and gene delivery by improv-
ing stealth properties. They demonstrate prolonged blood circulation and can induce maturation of dendritic cells, increase infiltration of CD4+ and CD8+
T cells, and cause immunogenic cell death. (Created by Biorender.com)
exosomes in cancer treatment. The following subsections of cancer. Myeloid-derived suppressor cells (MDSCs) in
delve into the exploration of the potential of endogenous the TME secrete exosomes, transferring miR-93-5p to
exosomes that are naturally secreted by cells in the body, suppress the STAT3 axis. Enrichment of miR-93-5p in
as well as bioengineered exosomes created in the labora- these exosomes, induced by IL-6, leads to MDSC dif-
tory for the treatment of cancer. ferentiation into M2 macrophages, facilitating colitis-
induced cancer development [474].
Endogenous exosomes When macrophages polarize into the M2 phenotype,
The primary source of exosome secretion includes nor- they release exosomes enriched with apolipoprotein E
mal cells, stromal cells, cancer cells, and immune cells. that reduces MHC-I expression, resulting in decreased
Exosomes secreted by breast cancer cells, for example, immunogenicity and induced immune resistance [475].
play a role in inducing immunotherapy by reprogram- Detecting exosomes with immunosuppressive/inductive
ming macrophage polarization. These exosomes carry functions involves recognizing their surface biomark-
PEDF, promoting M1 macrophage polarization by ers. Exosomes positive for PD-L1 are implicated in sup-
increasing CD80, IRF5, MCP1, and IL-1β levels, while pressing immune reactions during cancer progression.
reducing CD206, Arg, TGM2, and TGF-β levels [473]. PD-L1 + exosomes stimulate CD8+ T cell exhaustion,
Despite the immunotherapeutic potential of exosomes, enhancing tumorigenesis during cancer metastasis [476].
there are endogenously-secreted exosomes that enhance The secretion of PD-L1 + exosomes involves intricate
M2 macrophages, thereby contributing to cancer pro- molecular pathways, where HMGB1 upregulates RIC-
gression. Inflammation, a risk factor for cancer, can initi- TOR mRNA levels through miR-200 family downregu-
ate cancer development, and the regulatory functions of lation, particularly miR-429. This HMGB1 and RICTOR
macrophages in inflammation can alter the pathogenesis crosstalk increases PD-L1 generation, promoting the
activity of PD-L1 + exosomes in cancer immunotherapy galectin-9 siRNA and oxaliplatin, induce immunogenic
[477]. cell death, recruit T lymphocytes, reduce Treg cells,
Although PD-L1 + exosomes have carcinogenic func- and promote M1 polarization of macrophages, contrib-
tions, other exosomes can suppress PD-L1 expression. uting to cancer immunotherapy [486]. Engineered M1
Considering the ability of exosomes to induce cancer macrophage-derived exosomes, targeting TAMs with
immunotherapy, they may be utilized as potential vac- IL4RPep-1, NF-κB p50 siRNA, and miR-511-3p, induce
cines in the future. Cancer-derived exosomes exhibit cancer immunotherapy by reprogramming macrophages
superior capabilities in dendritic cell maturation and and restricting cancer proliferation [487]. Considered as
MHC cross-presentation, compared to cytotoxic T biocompatible carriers, exosomes may be used to mod-
lymphocytes. Furthermore, exosomes can reduce Treg ify other nanoparticles. Combining exosomes and lipo-
cell numbers in cancer immunotherapy by suppress- somes enhances gene delivery, suppresses CD47 signal,
ing PD-L1 expression [478]. This insight suggests that and increases CD8+ T cell potential. This strategy has the
bioengineered exosomes, specifically designed to target potential for clinical applications in cancer immunother-
dendritic cells, may serve as effective vaccines in can- apy [488]. Table 4 is a summary of the use of exosomes in
cer therapy. Although the discussion on bioengineered cancer immunotherapy.
exosomes is reserved for the next section, it is notewor-
thy that cells can be engineered to secrete exosomes for Stimuli-responsive nanostructures for cancer
cancer immunotherapy. For example, the nuclei of can- immunotherapy
cer cells introduced to M1 macrophages can lead to the pH-sensitive nanostructures
secretion of chimeric exosomes, selectively accumulating Smart nanoparticles responsive to TME stimuli may be
in lymph nodes and priming T cells to stimulate immune used to generate targeted delivery systems. Their multi-
reactions against cancer cells [479]. Therefore, exosomes functionality stems from changing structures in response
are potential regulators of the immune system in cancer to TME stimuli, facilitating cargo release at the tumor
[480]. Exploring the regulation of exosome secretion and site. The TME, because of its acidic pH, is distinctive
biogenesis from cells opens new avenues for controlling from normal cells, making pH-sensitive nanoparticles
cancer immunotherapy. ideal for cancer immunotherapy. Nanoparticles have
been synthesized using a PLA-b-PEG core and a cytosine
Bioengineered exosomes (C)-rich i-motif DNA surface to produce the so-called
Exosomes are used in cancer therapy because they are nanovaccines. They are used to deliver cyclic dinucleo-
naturally present in the body, making it less likely for tides such as cyclic dimeric guanosine monophosphate
them to be identified as foreign and cleared. Their high (CDG) to endosomes, accelerating anti-tumor immunity
biocompatibility allows effective cargo delivery and test- and preventing TME immunosuppression. In TME’s mild
ing in clinical trials. Dying cancer cell-derived exosomes, acidic pH, a conformational switch releases cargo, while
modified with MART-1 peptide and CCL22-siRNA, physiological pH minimally increases CDG release. These
induce T cell-mediated responses and suppress Treg pH-sensitive nanoparticles protect CDG from enzymatic
expansion [481]. Bioengineered exosomes can produce degradation, releasing the cargo into the cytoplasm, and
persistent immunity against cancer cells, and this paves stimulating polarization of macrophages into the M1
the way for the development of bio-based vaccines. Bio- phenotype [504].
engineered exosomes, painted with HMGB1, stimulate A groundbreaking achievement in cancer immuno-
dendritic cells, enhance immunogenicity, and induce therapy involves the creation of prodrug nanoparticles
long-term immunity against cancer. These exosomes for cargo delivery. These nanoparticles release cargo
accumulate in lymphoid tissues and enhance T cell func- in response to the pH of the TME. An innovative self-
tion, inducing long-term immunity and suppressing cascaded unimolecular prodrug was designed, com-
cancer progression [482]. Another approach involves prising an acidic pH-activatable doxorubicin, and an
functionalizing exosomes via CpG DNA to stimulate aggregation-induced emission luminogen (AIEgen) pho-
dendritic cells and enhance antigen presentation, show- tosensitizer linked to a caspase-3-responsive peptide.
casing their co-delivery ability in synergistic cancer This engineered prodrug exhibits dual functionality- it
immunotherapy [483, 484]. can actively release doxorubicin in the acidic TME and
Fusogenic exosomes have been synthesized to address initiate apoptosis-related caspase-3 activation. Further-
cancer cells escaping the immune system due to self- more, the activated caspase-3 can induce the release
recognition. These exosomes introduce viral antigens, and in-situ aggregation of photosensitizers. This process
stimulate dendritic cells, and present antigens to T lym- enhances dendritic cell maturation, increases CD8+ T cell
phocytes for CD8+ T cell cross-priming [485]. Exosomes numbers, and prevents metastasis to lung tissue [505].
from bone marrow-mesenchymal stem cells, loaded with
Table 4 Application of exosomes in cancer immunotherapy
Exosome Cargo Cancer type Cell line Remark Refer-
source ence
Dendritic cell Neoantigens Melanoma B16F10 cells Delivery of cargo to the lymph nodes and stimulation of T- and B-cell immune responses [489]
High biocompatibility
Improving survival of animal model
Suppressing proliferation and delayed tumor relapse
Glioblastoma LncRNA Glioblastoma Human Stimulation of microglia to generate and secrete complement C5 in chemotherapy resistance development [490]
glioma cell line
LN229, mouse
glioma cell line
GL261, human
microglial cell
line HMC3, and

mouse microg-
lial cell line BV-2
M1 HOTTIP Head and neck Hep-2 cells TLR5/NF-κB overexpression to impair progression of head and neck cancer [491]
macrophage cancer
CD45RO- CD8+ - Endometrial Ishikawa, RL95-2 The exosomes suppress estrogen-induced endometrial cancer progression through miR-765 release [492]
T cell cancer and KLE cells
(2024) 17:16
M1 SN38 Breast cancer 4T1 cells Cancer-targeting ability and prolonging blood circulation [493]
macrophage MnO2 Stimulating M1 polarization of macrophages
Increasing recruitment of NK cells
γδ-T cells - Nasopharyngeal NP69, HK-1 and Elimination and killing tumor cells [494]
cancer NPC43 cells Stimulation of FasL and DR5/TRAIL axis
Suppressing cancer growth
Increasing survival of animal model
Apoptosis induction
Increasing migration of T cells to the tumor site through CCR5 upregulation
- - Breast cancer 4T1 cells The smart and bioengineered exosomes with CD62L and OX40L can induce T cells and suppress Treg cell function [495]
Dendritic cells - Melanoma B16-OVA cells Functionalization of exosomes with anti-CD3 and anti-EGFR to bind to T cells [496]
iPSCs and Doxorubicin Gastric cancer MFC cell line Delivery of chemotherapy drug [497]
dendritic cells Tumor-targeting ability
exosomes Recruitment of immune cells to the TME
Cancer cells Paclitaxel Breast cancer 4T1 cells Development of liposome-exosome conjugate with high biocompatibility to increase the number of CD8+ T cells [498]
Cancer cells - Breast cancer 4T1 cells A combination of oxygenated water and cancer-secreted exosomes induce anti-tumor responses and suppress angio- [499]
genesis and invasion
Cancer cells - Pancreatic PANC-1 cells Exosomes reduce the levels of HLA-DR on the surface of CD14 + monocytes to cause immunosuppression through regu- [500]
cancer lation of STAT3, stimulation of arginase expression and ROS
M1 Docetaxel Breast cancer 4T1 cells The docetaxel-loaded exosomes stimulate cancer immunotherapy through M1 polarization of macrophages [501]
macrophages
Dendritic cells siRNA Melanoma B16-F10 cells BRAF siRNA delivery by exosomes to induce T lymphocytes [502]
HEK 293T cell Chlorin e6 Prostate cancer RM-1 cells The exosomes preferentially accumulate in the tumor site and induce dendritic cell maturation [503]
(Ce6) and im- Increasing levels of CD80 and CD86 as biomarkers of dendritic cells
mune adjuvant Inducing M1 polarization of macrophages
Page 26 of 48
R848
Mounting evidence supports the combination of che- immune cell infiltration, dendritic cell stimulation, and T
motherapy and immunotherapy using pH-sensitive cell recruitment for cancer immunotherapy [511]. Table 5
nanoparticles for cancer suppression. For example, summarizes the application of pH-sensitive nanoparticles
poly(L-histidine) (PHIS) has been used to encapsulate in cancer immunotherapy.
R848, forming pH-sensitive PHIS/R848 nanocores. Con-
jugating doxorubicin to hyaluronic acid creates prodrug Redox-sensitive nanoparticles
nanoparticles that coat PHIS/R848. These nanocarriers Redox-sensitive nanoparticles are carriers that release
undergo a switch from hydrophobic to hydrophilic in cargo in response to redox imbalances in the TME. The
response to pH change, releasing R848 to modulate the development of these nanoparticles involves introducing
immune system. At pH 5.5, the hydrazone bond cleaves, redox-sensitive bonds, such as disulfide bonds. They have
releasing doxorubicin. The latter is internalized into found application in cancer immunotherapy, capable of
tumor cells via endocytosis. This activates the immune stimulating various immune cells.
system and suppresses cancer proliferation [506]. Multifunctional nanocarriers with redox-sensitive fea-
Metal-based nanoparticles can also be designed to tures, comprising toll-like receptor agonists, catalase, and
decompose in response to TME pH. A human serum PD-L1-siRNA, have been designed for cancer therapy.
albumin-coated zeolite imidazolate framework-8 has These nanoparticles induce M1 polarization of macro-
been developed for the delivery of a photosensitizer phages, increase ROS production, downregulate PD-L1
(HPZ), for selective recognition of the TME [507]. This expression, and enhance CD8+ T cell functions by sup-
framework enables rapid elevation of zinc ion concentra- pressing Treg cells [525].
tions while ensuring controlled release of the encapsu- Clinical application of immunotherapy hinges on using
lated photosensitizer. Under physiological pH (7.4), HPZ biocompatible and long-term safe nanostructures like
exhibits a size of approximately 170 nm, decreasing sig- micelles. Micelles containing doxorubicin and R848, a
nificantly to less than 10 nm in acidic conditions (pH 6.5). TLR7/8 agonist, were experimentally used as nanovac-
The acid-induced decomposition of HPZ prompts a swift cines. Elevated glutathione levels in the TME trigger
increase in zinc ion concentration, exerting potent cyto- micelle decomposition, releasing cargo and inducing
toxic effects against colorectal, breast, and pancreatic immunogenic cell death, dendritic cell stimulation, and
cancers. Intravenous administration of HPZ in a CT26 accelerated immune responses. Additionally, redox-
tumor-bearing mouse model results in the expansion of responsive polymers and an A2AR antagonist within
T helper and cytotoxic T cells, and reduction in the Treg micelles suppress adenosinergic signaling to activate NK
cell population. These changes lead to a significant inhi- and CD8+ T cells in cancer immunotherapy [526].
bition of tumor growth. Cationic polymer dots, known for their small particle
While the primary focus of this section is to assess size, imaging capabilities, and drug delivery potential,
the role of nanoparticles in cancer immunotherapy, it is have seen extensive use in biomedicine. PEI600-modified
worth mentioning that microneedle arrays, composed of redox-sensitive hyperbranched poly(amido amine) nano-
tiny needles, can also be used for sustained cargo deliv- structures, partially carbonized with polymer dots, were
ery. pH-sensitive nanoparticles can be incorporated into used for carrying ovalbumin. These structures enhance
microneedles, facilitating sustained release for hyperac- splenocyte proliferation, elevate cytokine levels (includ-
tivating the immune system and creating nanovaccines ing IL-12 and IFN-γ), promote dendritic cell maturation,
[508]. Hydrogels are also available for sustained cargo and increase CD4+ and CD8+ T cell counts, as well as T
delivery. For example, nanoparticles can be embedded lymphocytes. Ovalbumin release from these structures is
in pH-sensitive hydrogels for delivering doxorubicin redox-responsive [527].
and JQ1 (a small molecular inhibitor) to induce immu- Given that both pH and redox serve as endogenous
nogenic cell death [509]. Of note, pH-sensitive biomi- stimuli, new nanocarriers have been developed that
metic nanocarriers, crafted from PLGA and coated with exhibit dual responsiveness. pH- and redox-sensitive
membranes from macrophages and cancer cells, can micelles containing ovalbumin, modified with PLH-PEG,
deliver FGL1-siRNA and metformin for cancer immuno- are used as cancer vaccines. These micellar nanostruc-
therapy. These biomimetic nanoparticles enhance cargo tures enable cytosolic delivery of ovalbumin through
endosomal escape, with metformin suppressing PD-L1 redox release, proton influx, micelle disassembly, and
through AMPK upregulation, and siRNA reducing FGL1 ultimately, a proton sponge effect and lysosome break.
expression to boost anti-cancer immunity through T cell These micelles enhance MHC-I rates, antigen presenta-
induction [510]. Given the impact of TME pH on tumori- tion, lymph node accumulation, and improve immune
genesis, pH regulators have been developed. Calcium reactions [528].
carbonate nanostructures neutralize TME pH by con-
suming lactate, promoting M1 macrophage polarization,
Photo-responsive nanoparticles and phototherapy nanostructures enhance T cell infiltration, inhibit the
Light serves as an exogenous stimulus in nanoparticle primary tumor, and show promising impacts in combina-
development, where laser irradiation induces bond cleav- tion with checkpoint inhibitors [532].
age to release the loaded cargo. This forms the basis of The combination of PDT and immunotherapy has
photodynamic therapy (PDT) and photothermal ther- shown promising results in cancer immunotherapy.
apy (PTT) for cancer ablation. In PDT, ROS production Although PDT and PTT have different mechanisms
induces cell death, while PTT causes cell death through of action, both can be combined with immunotherapy
hyperthermia. Combining phototherapy with immuno- to expedite the immunotherapeutic process by expos-
therapy can enhance cancer suppression. Two methods ing antigens or inducing cell death to stimulate immune
are utilized, including a combination of phototherapy responses. Photodynamic therapy is preferred over PTT
and immunotherapy or stimulation of phototherapy- due to potential hyperthermia effects on normal tissues.
mediated immunotherapy. Both methods offer a high However, when tumor-targeted nanoparticles are devel-
likelihood of tumor suppression, improving the fight oped, they can precisely execute PDT in the tumor site,
against cancer. PLGA nanoparticles loaded with R837, effectively killing cancer cells. Various nanoenzymes with
docetaxel, and PB agents are used for immunotherapy cancer cell accumulation can be developed to induce
and PTT. These nanoparticles are modified with cancer PDT and enhance cancer immunotherapy.
cell membranes for enhanced effectiveness. R837 stimu- A nanoparticle core was created by connecting pacli-
lates dendritic cell maturation, and docetaxel increases taxel drugs through a disulfide bond (PTX-SS-PTX),
M1 polarization of macrophages, impairing the immuno- with P18 as a photosensitizer connected to MPEG-
suppressive TME. This leads to increased infiltration of CPPA-b-P(M4). In response to glutathione, the disul-
cytotoxic T lymphocytes in the TME for effective cancer fide bond degrades, and laser irradiation in response to
immunotherapy [529]. ROS increases singlet oxygen generation, releasing high
Similar to doxorubicin, which induces immunogenic mobility group box 1 (HMGB1) due to GSDME activa-
cell death, docetaxel has shown potential in cancer tion. HMGB1 releases and pyroptosis induction leads
immunotherapy by regulating TAM polarization. CuS to dendritic cell maturation, educating naïve T cells in
nanoparticles with NH2 functional groups, function- lymph nodes, expanding T cells, and developing memory
alized with folic acid and conjugated to PEI-PpIX for T cells for cancer immunotherapy [533].
enhanced solubility, deliver docetaxel and CpG, inducing For PDT stimulation, the photosensitizer is loaded into
PTT and immunotherapy. These nanoparticles exhibit nanoparticles. Recent studies have shown the potential of
excellent photothermal conversion ability upon exposure herbal medicine in cancer treatment. Mesoporous silica
to 650 and 808 nm laser irradiation and induce M1 polar- nanoparticles modified with PEG can carry both chlorin
ization of macrophages through the function of docetaxel e6 and astragaloside III, stimulating NK cells and sup-
in cancer immunotherapy [530]. pressing cancer cell growth. These nanoparticles accumu-
Beyond combining immunotherapy and PTT, it is pos- late in the tumor site, increasing immune cell infiltration,
sible to induce immune reactions resulting from PTT. promoting the activity and cytotoxicity of CD8+ T cells
Tumor cell killing and antigen release can accelerate and NK cells, and impairing tumorigenesis [534].
immune reactions. A peptide-photosensitizer conjugate, Liposomes are also potential nanocarriers in cancer
developed from anti-PD-L1 peptide, cleavable by MMP- immunotherapy. Liposomes carrying IPI-549 as a PI3Kγ
2, and purpurin 18 as a photosensitizer, accumulates in inhibitor and chlorin e6 as a photosensitizer induce
the tumor site. MMP-2 enzyme degradation releases ROS generation after irradiation, facilitating immuno-
the peptide, causing antigen release. Irradiation induces genic cell death and improving the potential of T lym-
dendritic cell maturation, migrating into lymph nodes, phocytes in eliminating cancer cells. IPI-549 delivery by
increasing T cell infiltration, suppressing metastasis to nanoparticles can decrease arginase-1 (Arg-1) and ROS
lung tissue, and eliciting anti-tumor immune responses levels, increasing apoptosis in MDSCs, and preventing
[531]. their suppressive function on T cells. In addition, these
Photo-responsive structures can also function as vac- nanoparticles decrease the infiltration of M2-polarized
cines. Chelation of Fe3+ ions with ovalbumin leads to macrophages and mature dendritic cells in cancer immu-
biomineralization into nanovaccines, embedding IR820 notherapy [535].
as a photosensitizer through electrostatic incorpora- In both nanoparticle-mediated PDT and PTT, the
tion. The presence of iron induces ferroptosis, mediat- most prominent mechanism is the stimulation of immu-
ing immunogenic cell death. Immunogenic cell death nogenic cell death to accelerate cancer immunother-
stimulates neoantigens and DAMPs, synergizing with apy. Increasing evidence highlights the application of
ovalbumin in cancer immunotherapy. Near-infrared irra- nanoparticle-mediated phototherapy and immunother-
diation induces PTT, enhancing immunotherapy. These apy in cancer suppression [536–540]. Table 6 summarizes
Table 5 pH-sensitive nanoparticles in cancer immunotherapy
Nanoparticle Cancer type/ Size (nm)/zeta Highlights Refer-
cell line potential (mV) ence
PEG/PEI/CAD Breast At a range of Delivery of doxorubicin and its release in a pH-sensitive manner [512]
nanoparticles cancer/4T1 cells 100–250 nm/at a Immunogenic cell death induction
range of 10–20 mV The acidity of the endosome induces cleavage of cis-aconityl
Recruitment of dendritic cells
Hollow silica Breast 100 nm/+11 mV Increased retention in response to low pH level of TME [513]
nanostructures cancer/4T1 cells Targeting mitochondria and increasing ROS levels
Stimulation of photodynamic therapy
Combination with checkpoint inhibitors mediates anti-tumor immunity
Dextran-mod- Breast 11.35, 112.4, and Presence of a borate ester bond as a pH-sensitive bond [514]
ified BLZ-945 cancer/4T1 cells ∼135.6 nm Immunogenic cell death induction
nanocarriers Dendritic cell maturation, TAM depletion and T cell infiltration

Manganese Melanoma/B16- 130 nm Mn2 + and 2-methylimidazole (2-MI) have been used to encapsulate ovalbumin with pH-sensitive features and the ability of dendritic [515]
nanoparticles OVA cells cell maturation in cancer immunotherapy
Mesopo- - 146 nm pH-sensitive feature and delivery of R848 [516]
rous silica Uptake of nanoparticles by antigen-presenting cells
nanostructures Stimulation of dendritic cells and boosting T cell-mediated immune responses
(2024) 17:16
Peptide- Breast 173.8 nm/-1.53 mV Functionalization of nanobubbles with anti-PD-L1 peptide [517]
functionalized cancer/4T1 cells Loading Ce6, metformin and perfluorohexane in nanobubbles
nanobubbles Accumulation of nanoparticles in acidic pH causes detachment of PEG ligands and then, exposure of peptide to suppress PD-L1
Hypoxia relief by metformin and increasing potential of Ce6 in cancer therapy
Increasing anti-tumor immunity and prevention of immunosuppression
Polymer-lipid Lymphoma/E. - The polymer-lipid-embedded liposomes release ovalbumin in response to pH and stimulate anti-cancer immunity by releasing oval- [518]
complexes G7-OVA cells bumin in the cytoplasm of dendritic cells
Polymer-modi- Lymphoma/E. 100 nm/−15.7 mV pH-responsive feature and cationic lipid inclusion [519]
fied liposomes G7-OVA cells and 1.3 mV at pH 7.4 Delivery of ovalbumin
and pH 5.5 Increasing cytokine generation
Antigen presentation through MHC-I and MHC-II
Liposome Lymphoma/E. 136, 108 and Modification of liposomes with polymer [520]
G7-OVA cells 115 nm/-0.87, -11 Destabilization of liposomes in pH 6
and − 6.1 mV Uptake of liposomes by dendritic cells
Delivery of ovalbumin to cytosol
Tumor growth suppression
Polymer-modi- Lymphoma/E. 97, 100, 88, 110, 108 Inclusion of cationic lipid and CpG-DNA [521]
fied liposomes G7-OVA cells and 109 nm/-18, Inducing dendritic cells to secrete cytokines
-19, -11, -63, -65 and Stimulation of antigen-specific immune responses
− 60 mV pH-sensitive feature
Biomimetic Breast 102.86 nm Coating manganese nanoparticles with hybrid membranes [522]
nanoparticles cancer/4T1 cells Membrane is developed from mesenchymal stem cell membrane and pH-sensitive liposomes
Targeted delivery of BPTES
Inducing STNG pathway and M1 polarization of macrophages
Relief of immunosuppression TME
Page 29 of 48
the nanoparticles causing PDT and PTT, and their com-
Refer-
[523]
[524]
ence
bination and relationship with immunotherapy. Figure 6
shows the application of stimuli-responsive nanocarriers
in cancer immunotherapy. Since the pre-clinical stud-
ies demonstrate the function of nanoparticles for can-
cer immunotherapy and tumor suppression, the clinical
application of nanostructures in cancer immunotherapy
has been performed to evaluate their potential [541].
Table 7 and table 8 summarize the clinical application of
nanoparticles in cancer immunotherapy.
An overview of various classes of nanoparticles in

cancer immunotherapy
Polymeric nanoparticles
Polymeric nanoparticles are among the most commonly
applied structures in cancer immunotherapy owing to
their biocompatibility, biodegradability, chemical stabil-
ity, water solubility, and high drug loading [564, 565]. The
PLGA, PGA, PLG, PEG, PEI and chitosan nanoparticles
have been widely used in cancer immunotherapy [566].
Moreover, such nanostructures have shown potential as
immunostimulatory adjuvants in cancer immunotherapy
[567–569]. Loading TLR7/8 agonists in PLGA nanostruc-
tures enhanced levels of CD40, CD80, and CD86 through
Increasing Th1 immune responses in tumor suppression
pH-sensitive liposomes deliver STING and TLR9 agonist
stimulation of bone marrow-derived dendritic cells and

subcutaneous administration of such nanoparticles stim-
ulated dendritic cells and CD8+ T cells [570].
Th1 cytokine production by dendritic cells
Lipid nanoparticles
Liposomes are among the promising nanocarriers for
Cytoplasmic delivery of antigen
drugs, genes and vaccines [571]. Until now, multiple

Stimulation of dendritic cells
kinds of liposomal nanostructures including 1,2-dioleoyl-

3-trimethylammonium-propane (DOTAP), 3β- (N- [N’,
N’-dimethyl aminoethane] - carbamoyl) cholesterol
(DC-Chol), and dimethyl diocta decylammonium (DDA)
Highlights
[572, 573] have been significantly applied for the antigen

exposure to APCs and providing vaccine adjuvants to
increase antigen-specific immune reactions [574, 575].
The dextran-functionalized liposomes with pH-sensitiv-
ity activity have shown high uptake by dendritic cells and
Melanoma/B16- 401, 754, 636 and
potential (mV)
157 nm/-50 mV
Size (nm)/zeta
they can provide cytosol delivery of ovalbumin to accel-

erate antigen-specific immune reactions and impair can-
674 nm
cer progression [576]. Furthermore, loading CpG-ODNs

as TLR9 agonist and 3,5-didodecyloxybenzamidine as
an adjuvant into liposomes can enhance dendritic cell-
mediated cytokine production to enhance antigen-spe-
Lymphoma/E.
Cancer type/
G7-OVA cells
cific immunity [521]. Micelles are among another kind of

OVA cells
cell line
lipid nanoparticles that can function as delivery systems

Table 5 (continued)
for antigen/adjuvant to improve potential of vaccines.

The polymeric hybrid micelles have been utilized for the
based polymers
Polysaccharide-
delivery of CpG-ODN and Trp2 to create a nanovac-

Nanoparticle
cine for targeting lymph nodes and enhancing the accu-

Liposomes
mulation of cargo in dendritic cells, triggering CD8+ T

cell-mediated immune responses and enhancing cancer and survival rates. However, challenges persist in the
suppression (melanoma) [577]. utilization of adjuvants and immunomodulatory agents.
This prompted the exploration of novel solutions, par-
Carbon nanoparticles ticularly through the application of nanoparticles. The
Carbon nanotubes (CNTs) have been shown to medi- intricate interactions within the TME play a pivotal role
ate immunostimulatory impacts in vitro and in vivo. The in influencing cancer cell responses to immunother-
oxidized multiwalled carbon nanotubes (MWCNT) have apy. In this context, nanoparticles designed for targeted
shown the ability for the delivery of cancer-testis antigen, delivery of immunomodulatory compounds and TME
known as NY-ESO-1 and CpG-ODNs. These structures remodeling have emerged as promising tools in cancer
showed uptake by dendritic cells and mediated power- immunotherapy.
ful CD4+ and CD8+ T cell-driven immune reactions to Nanoparticles address the current challenges in cancer
impair melanoma progression [578]. Furthermore, the immunotherapy by demonstrating the capability to regu-
co-delivery of ovalbumin and CpG-ODN, as well as anti- late TME components, altering the trajectory of tumor
CD40 Ig as immunoadjuvants by MWCNTs has shown cell progression, and mitigating the immunosuppres-
potential in accelerating T cell responses and suppressing sive milieu in cancer. Nanostructures designed for TME
melanoma progression [579]., remodeling can increase the infiltration of cytotoxic T
cells, stimulate dendritic cells, induce M1 macrophage
Metal nanoparticles polarization, and inhibit MDSCs. Furthermore, nanopar-
Gold nanostructures are promising factors in cancer ticles serve as effective carriers for delivering adjuvants
immunotherapy owing to their characteristics, including and other immunomodulatory compounds, such as
biocompatibility, adjustable surface chemistry, and ease drugs or genes, in cancer immunotherapy.
of controlling size and shape [580]. The gold nanostruc- A significant breakthrough in nanoparticle develop-
tures have shown potential in inducing differentiation of ment for cancer immunotherapy lies in the creation
macrophages into dendritic-like cells to enhance T cell of biomimetic nanocarriers, incorporating functional-
proliferation and promote cytokine release [581]. Fur- ized membranes derived from red blood cells, tumor-
thermore, the gold nanostructures have shown incred- associated macrophages, cancer-associated fibroblasts,
ible potential to act as adjuvants for enhancing antibody and tumor cells. In addition, the utilization of exo-
generation [582]. The potential of gold nanoparticles in somes, whether naturally secreted by cells or bioengi-
cancer therapy via TME modulation has been revealed neered in the laboratory, holds promise in regulating the
[583, 584]. The surface of hollow gold nanostructures has immune system in cancer therapy. Nanoparticles exhibit
been functionalized with CpG-ODNs to enhance their the capacity to diminish the number of Treg cells and
cellular uptake and enhance function in the induction of MDSCs, preventing immunosuppression. Moreover,
immune responses, including enhancing TNF-α secre- nanoparticle-induced immunogenic cell death promotes
tion [585]. The silica nanoparticles have also been applied the activation of dendritic cells, facilitating their migra-
widely in biomedicine for imaging [586], specific target- tion into lymph nodes to stimulate T cells for cancer
ing of cancer [587], and delivery of drugs and genes [588]. immunotherapy.
The mesoporous silica nanoparticles have been applied Stimuli-responsive nanocarriers, particularly pH- and
for antigen delivery and acted as vaccines to induce redox-sensitive nanoparticles, enhance the potential of
humoral- and cell-driven immune reactions while having cancer immunotherapy. Photo-responsive nanoparticles,
high biocompatibility and lacking toxicity [589]. The hol- through photothermal and photodynamic therapy, con-
low mesoporous silica nanoparticles have been shown to tribute to the augmentation of cancer immunotherapy
be biodegradable and are capable of TME remodeling in by inducing immunogenic cell death, regulating dendritic
cancer immunotherapy [361]. According to these studies, cells and T cells, and promoting M1 polarization of mac-
various categories of nanostructures demonstrate prom- rophages. This multifaceted approach highlights the ver-
ising characteristics in cancer immunotherapy, and all satility and promise of nanoparticles in advancing cancer
of them have shown potential in TME remodeling. The immunotherapy.
next step for the clinical application of these nanocarriers The clinical application of nanoparticles involves sev-
depends on their biocompatibility and long-term safety eral crucial considerations [590]. Once we comprehend
that lipid nanoparticles are at the front line. the potential of nanoparticles in cancer immunotherapy,
translation of these technologies, advancements, and
Conclusion and challenges findings to the clinical setting becomes imperative. Clini-
Cancer immunotherapy and the development of vaccines cal trials involving immunotherapy for cancer patients
have ushered in a new era in cancer treatment, instilling are already underway. In the context of solid tumors and
hope in patients and significantly enhancing prognosis their clinical treatment, leveraging nanoparticle-induced
Table 6 Nanoparticle-mediated PDT and PTT and their relationship with cancer immunotherapy
Nanoparticle Cancer type/ Size (nm)/zeta po- Outcome Ref-
Cell line tential (mV) er-
ence
Nano-PROTACs Breast 40 and 80 nm/ The nanoparticles have been comprised of PpIX as photosensitizer and SHP2-targeting PROTAC peptide (aPRO)
cancer/4T1 The stimulation of aPRO occurs as a response to upregulation of caspase-3 [542]
cells Targeted degradation of SHP2 through ubiquitin-proteasome system
SHP2 depletion suppresses immunosuppressive pathways, including CD47/SIRPα and PD-1/PD-L1, to improve anti-cancer functions of
macrophages and T cells
MRC Breast 38.69 ± 0.20 Co-delivery of RGX-104 as an immune agonist and chlorin e6
nanoparticles cancer/4T1 Stimulation of ApoE by RGX-104 to impair the function of MDSCs and accelerate pyroptosis [543]
cells Chlorin e6-induced PDT to facilitate oxidative damage and enhance immunogenicity
Ru(II)-modified 4NQO-Oral 40 nm/ −7.41 ± 1.22 Loading HIF-1α-siRNA in nanoparticles
TiO2 nanocarriers cancer and + 27.65 ± 2.46 mV Stimulation of PDT and inducing lysosomal damage [544]
Downregulation of HIF-1α and enhancing killing of oral cancer
Stimulation of CD4+ and CD8+ T cells
PDA-FA Colon cancer/ 130 nm/-14.29 mV Delivery of CpG as immunomodulatory to induce dendritic cell maturation and increase T cell activity
nanoparticles CT26 cells Suppressing Treg cells and MDSCs [545]
PTT induction
(2024) 17:16
Copper sulphide Melanoma/ 28 nm/30.5 mV Delivery of Cas9 ribonucleoprotein to target PTPN2

nanoplatforms B16F10 cells Downregulation of PTPN2 to increase infiltration of CD8+ T cells [546]
Increasing levels of IFN-γ and TNF-α
Improving immune-sensitivity
Polymer Breast 40 nm/-31 mV Doping with TLR agonist as an immunomodulatory adjuvant
nanoadjuvants cancer/4T1 Presence of lipid shell response to temperature [547]
cells The PTT potential in response to NIR-II
Immunogenic cell death induction and release of TLR agonist
Upregulation of TLR7/TLR8 and stimulation of immunogenic cell death enhance dendritic cell maturation and amplification of anti-
cancer immune responses
Nanoenzymes Breast 100 nm Cu-doped MoOx (CMO) nanozyme comprises the core that is coated with cancer cell membrane
cancer/4T1 Increasing the tumor accumulation and nanozymes causes oxidative damage through increasing ROS generation [548]
cells PTT causes immunogenic cell death to activate the immune system
Gold nanorod Colon cancer/ 66.48 ± 1.41, The 808 nm laser irradiation causes PTT
CT26 cells 76.73 ± 4.6, 93.72 ± 2.7, Stimulation of immune cells in the lymph nodes [549]
and 116.8 ± 6.5 nm/26
mV
AIE Breast 110.3 nm/+10.68 mV Modification with cancer cell membrane
cancer/4T1 Stimulation of immunogenic cell death [550]
cells Increasing ROS generation through PDT
Polymer Breast 42 and 50 nm/-19.9 Stimulation of PTT
nanoagonist cancer/4T1 mV Increasing immunotherapy and induction of immunogenic cell death [551]
cells
Antigen-captur- Breast 41.1 nm Stimulation of phototherapy under NIR irradiation
ing nanoparticles cancer/4T1 Increasing antigen uptake and presentation [552]
cells Suppressing cancer progression
Page 32 of 48
phototherapy is recommended to enhance immune
ence
[553]
[554]
Ref-
er-
responses and stimulate dendritic cells along with their
maturation.
Last, but not least, it is essential to assess the biocom-
patibility of nanoparticle-induced immune responses
to prevent systemic immune reactions against normal
NIR irradiation increases dendritic cell activation and then, they migrate into lymph nodes for the stimulation of CD8+ T cells
cells. Evaluation of delivering immunomodulatory agents
alongside chemotherapy drugs should be conducted
to determine the synergistic impact on cancer therapy.
However, careful consideration must be given to whether
the associated side effects are tolerable for patients.
Therefore, assessing the biocompatibility and toxicity
profile of nanoparticles stands out as a critical aspect of
their clinical application.
Currently, a high number of studies have focused on
the clinical utilization of nanostructures for boosting
immunotherapy [591]. One of the most prominent draw-
backs is that currently developed nanoplatforms are in
phase I or II. The present review provided the possible
interaction and function of nanoparticles with TME
components and immune cells to induce cancer immu-
notherapy that can be used in clinics. In most cases, ani-
mal models have been utilized to evaluate the potential
of nanoparticles in cancer immunotherapy, making it
Delivery of anti-PD-L1 and galunisertib by nanocages
hard to translate to humans. The selection of humanized

animal models can improve the chance of translation
Loading them into thermosensitive hydrogels
Stimulation of PTT to cause immunotherapy
into the clinic. Moreover, the appropriate nanoparticles

should be chosen for cancer immunotherapy. In this
way, it is suggested to use FDA-approved agents such as
polymers or lipid nanoparticles to accelerate the pace of
clinical translation and immune regulation. The biosafety,
tolerability, and reproducibility of nanocarriers should
also be considered for clinical application. In recent
years, a high number of nanoparticles have been intro-
duced into clinics for the treatment of cancers, including
lipid-based nanoparticles (generic name: JVRS-100) for
Outcome
the treatment of leukemia (NCT00860522), liposomes

for the treatment of lymphoma, melanoma, breast, ovar-
ian and prostate cancers (NCT03349450, NCT01052142,
52 ± 3 nm/ -24 ± 2 mV
NCT01095848), PLGA nanoparticles for the treatment of

Size (nm)/zeta po-
metastatic melanoma (NCT01753089) and colloidal gold

120 nm/-23 mV
tential (mV)
structures for the treatment of advanced solid tumors

[592]. However, all of these nanoparticles have been eval-
uated in phase I and II studies.
Taking everything together, there are a number of
points that should be considered for the application of
Colon cancer/
Cancer type/
cancer/4T1
nanoparticles in cancer immunotherapy [593]. Cur-

CT26 cells
Cell line
rently, cancer immunotherapy is mainly based on the

Breast
Table 6 (continued)
cells
application of nano-scale delivery systems for con-

ventional immunotherapeutic compounds, including
rus quantum dot
Gold nanocages
Black phospho-
antibodies, recombinant proteins, and small molecular-

Nanoparticle
nanovesicles
based immune agonist, adjuvant, or inhibitor. The ratio-

nale for the application of nanoparticles is to improve
the pharmacokinetic profile of immunotherapeutic
Fig. 6 Stimuli-responsive nanocarriers in cancer immunotherapy. Nanoparticles that respond to pH, redox, or light can release cargo to induce apoptosis,
DNA damage, and regulation of molecular pathways. Moreover, stimuli-responsive nanocarriers stimulate immunogenic cell death to increase dendritic
cell maturation. They migrate into lymph nodes and increase activation of T cells
Table 7 The application of nanoparticle-based immunotherapy in clinical studies [541, 555–557]

Nanoparticle Phase Remark Reference
RNA-lipoplexes Phase I Increasing maturation of dendritic cells and increasing T cell [558]
response
miR-34a-loaded liposomes Phase I Reduction in the expression of immune evasion genes [559]
miR-4157-loaded lipids Phase I Stimulation of neoantigen-specific T cells and increasing anti- [560]
Iron oxide nanostructures Not Increasing M1 polarization of macrophages from M2 phenotype [256]
applicable
Paclitaxel-loaded lipid core nanostructures Phase II Enhancing dendritic cell maturation [561, 562]
Doxorubicin-loaded anti-EGFR immunoliposomes Phase II Stimulation of immunogenic cell death NCT02833766
Suppressing EGFR-induced growth signaling
Plasmid DNA complex-loaded cationic liposomes Phase I Stimulation of the immune system NCT00860522
Combination of anti-PD-1 and hafnium oxide Phase I Increase in tumor cell death, promotion of immunogenic cell NCT03589339
nanostructures death, and induction of the immune system [563]
agents, diminish the side impacts, prevent the cytokine including nanoparticle-mediated immunogenicity, bio-
storm by immune hyperactivation, and ameliorate defi- compatibility and engineering aspects regarding thera-
ciency in immune responses. Moreover, nanoparticles peutic compound loading in nanostructures. Moreover,
are promising for reversing immunosuppression and several nanoparticles have anti-cancer activity, caus-
preventing immune evasion. Although this is an inter- ing synergistic impact with immunotherapeutics. One
disciplinary field combining biology and engineering, of the most important features of nanoparticles is
a number of factors should be carefully investigated, their ability for controlled release of therapeutics. The
Table 8 The challenges regarding the application of nanoparticles in cancer immunotherapy
Nanoparticles Benefits Challenges
Polymeric • Targeted delivery of cargo to improve the therapeutic index and reduce the systemic side effects • The development of nanoparticles with desirable size, charge, and targeting
nanoparticles • Prolonged release of drugs capacity is challenging
• Potential in the delivery of various cargoes including small molecule drugs, proteins, peptides, and • Strict rules regarding clinical application
nucleic acids • Unexpected interactions with the immune system
• Increased stability of drugs and preventing degradation • Challenges in the scale-up generation, storage and stability
• Stimulation of the immune system
• Biocompatibility and biodegradability
Lipid • Efficient delivery of genetic tools including mRNA, siRNA, and DNA • Complex manufacturer production, especially the development of nanopar-
(2024) 17:16
nanoparticles • Targeted delivery ticles for gene delivery

• Protection of cargo • They require ultra-low temperatures to preserve their stability
• Long-term biocompatibility and safety • Immunogenicity that can lead to inflammation and other side effects
• Adjuvant impact that a number of lipid components can function as adjuvants and increase anti- • Low loading capacity
Metal • Targeted delivery of drugs and high loading and encapsulation efficiencies • The biodistribution of metal nanostructures is challenging along with their
nanoparticles • Application for photothermal therapy, since a number of nanostructures such as gold nanocarriers clearance from the body
can absorb light and cause photothermal-mediated tumor ablation • The metal nanostructures possess high cytotoxicity and poor biocompatibility
• Delivery of immunomodulatory agents for cancer immunotherapy • The chance of inflammation and immune reactions
• Synergistic therapy through a combination of drug delivery and photothermal therapy • Stability and toxicity towards normal cells
• Imaging and biosensing
Carbon • High drug-loading potential for the delivery of drugs, proteins, and genetic tools • The toxicity and poor biocompatibility
nanoparticles • Application in photothermal and photodynamic therapy • The changes in the biodegradation of carbon nanoparticles, leading to their
• Imaging and biosensing of cancer biomarkers long-term accumulation
• Complexity in the generation of nanoparticles at a large scale and achieving the
desirable physicochemical properties including size, zeta potential and others
• Heterogeneous biological functions among the various classes of carbon nano-
materials including tubes, dots and sheets
Page 35 of 48
FDA U.S. Food and Drug Administration

hyperactivation of immune systems using immune ago- CTLA4 Cytotoxic T-Lymphocyte Antigen 4
nists or adjuvants can affect normal cells and tissues. PD-1 Programmed Cell Death Protein 1
Therefore, the delivery of therapeutics should be per- PD-L1 Programmed Death-Ligand 1
TAMs Tumor-Associated Macrophages
formed in a controlled manner and safe levels should be Th1 Type 1 T Helper Cell
delivered. Moreover, the rapid or burst release of immu- IL-4, IL-10, IL-13 Interleukin-4, Interleukin-10, Interleukin-13
notherapy compounds is not effective in providing long- M1 M1 Macrophages
M2 M2 Macrophages
term anti-cancer immunity. A number of nanoparticles TGF-β Transforming Growth Factor-Beta
are promising for the controlled release of therapeutic α-SMA Alpha-Smooth Muscle Actin
compounds, including PLGA nanostructures that, upon NK cells Natural Killer Cells
IFN-γ Interferon-Gamma
degradation of the polymer, the release of the immuno- B cells B Lymphocytes
therapeutic compound occurs [594, 595]. Biocompatibil- T cells T Lymphocytes
ity has been another important factor in pre-clinical and PD-1 Programmed Cell Death Protein 1
TCM Central Memory T Cells
clinical studies [596]. Along with controlling the toxicity TEM Effector Memory T Cells
of immunomodulatory factors, including recombinant TRM Resident Memory T Cells
cytokines [597–599], the physicochemical characteris- TSCM Stem Cell Memory T Cells
TE Effector T Cells
tics of nanostructures including size, shape and thermal Th1 Type 1 T Helper Cell
conversion ability, among others, should be adjusted in a IFN-γ Interferon-Gamma
manner to reduce the side effects of nanoparticles [600, TCM Central Memory T Cells
CEMIP Cell Migration-Inducing Hyaluronidase 1
601]. In this way, the toxicity of nanoparticles in vitro USP22 Ubiquitin-Specific Peptidase 22
and in vivo, hemocompatibility, effect on major organs RNF31 Ring Finger Protein 31
including liver and kidney, and metabolic pathways YAP Yes-Associated Protein
CDKN2A/B Cyclin-Dependent Kinase Inhibitor 2 A/B
should be investigated [602]. The surface functionaliza- SUSD6 Sushi Domain Containing 6
tion of nanoparticles is another important factor in can- TMEM127 Transmembrane Protein 127
cer immunotherapy. The surface functionalization can WWP2 WW Domain Containing E3 Ubiquitin Protein Ligase
2
affect the intracellular uptake of nanostructures and even mTORC1 Mechanistic Target of Rapamycin Complex 1
their processing [603]. Furthermore, since nanoparticles CD248 Cluster of Differentiation 248
have been applied for antigen capture, the surface charge, OPN Osteopontin
SERPINE1 Serpin Family E Member 1
hydrophobicity and hydrophobicity can change the func- RGS5 Regulator of G Protein Signaling 5
tion of nanostructures in cancer immunotherapy [299]. apCAFs Antigen-Presenting Cancer-Associated Fibroblasts
Another factor is that the nanostructures can specifically rCAFs Restraining Cancer-Associated Fibroblasts
iCAFs Inflammatory Cancer-Associated Fibroblasts
target the lymphoid tissues or immune cells to enhance PRDM1 PR Domain Zinc Finger Protein 1
the potential of drugs in cancer immunotherapy [604]. ZnCDA Zinc Chlorodipyridine Acetate
Polymeric nanoparticles have shown high potential in STING Stimulator of Interferon Genes
ROS Reactive Oxygen Species
vascular escape, infiltration into tissues and lymphatics TLR4 Toll-Like Receptor 4
and targeting lymphocytes, while liposomes show high MyD88 Myeloid Differentiation Primary Response 88
uptake by phagocytic cells, including macrophages [603]. Fe3O4-SAS@PLT Ferrimagnetic Mesoporous Silica Nanoparticles
Loaded with Sulfasalazine and Functionalized with
In addition, these nanoparticles demonstrate high safety Platelets
along with capacity in cancer immunotherapy [605– CSF1 Colony Stimulating Factor 1
608]. Notably, the nanoparticles can be considered as CSF1-R Colony Stimulating Factor 1 Receptor
SIRPα Signal Regulatory Protein Alpha
immune potentiates in which metal nanoparticles, virus- MCSF Macrophage Colony-Stimulating Factor
like nanostructures and other categories can stimulate MAPK Mitogen-Activated Protein Kinase
immune responses through induction of B and T cells PEGylated liposomes Polyethylene Glycol-coated Liposomes
R848 Imiquimod analog
[603, 609] that is highly dependent on the size and sur- CCL5-siRNA Chemokine (C-C motif ) Ligand 5 Small Interfering
face charge of nanostructures [366, 610, 611]. However, RNA
carbon nanostructures have shown immunosuppressive Ce6 Chlorin e6
PFC Perfluorocarbon
impacts in some cases [612, 613]. Therefore, the intro- MIP-3β Macrophage Inflammatory Protein-3β
duction of nanoparticles for thr purpose of cancer immu- Au@PG Gold Nanoparticles coated with Polyaniline-Glucose
notherapy is of importance. CaCO3 Calcium Carbonate
DGL-ZA Dendrigraft Poly-L-Lysines-Zoledronate
Abbreviations MMP2 Matrix Metalloproteinase 2
ICIs Immune Checkpoint Inhibitors cGAS/STING Cyclic GMP-AMP Synthase/Stimulator of Interferon
TME Tumor Microenvironment Genes
NFAT Nuclear Factor of Activated T Cells PLGA Poly(lactic-co-glycolic acid)
TOX Thymocyte Selection-Associated High Mobility CTL Cytotoxic T Lymphocyte
Group Box Protein MDSCs Myeloid-Derived Suppressor Cells
NR4A Nuclear Receptor Subfamily 4 Group A Treg cells Regulatory T cells
PARP Poly(ADP-ribose) Polymerase Competing interests

AMPKα/mTOR AMP-Activated Protein Kinase Alpha/Mammalian The authors declare no competing interests.
Target of Rapamycin
GITR Glucocorticoid-Induced Tumor Necrosis Factor Author details
1
Receptor Department of Thoracic Surgery, Tangdu Hospital, Air Force Medical
PLG Poly(lactide-co-glycolide) University, 569 Xinsi Road, Xi’an 710038, China
2
PLH Poly-L-Histidine Department of Rehabilitation Medicine, Chongqing Public Health
IDO Indoleamine 2,3-dioxygenase Medical Center, Chongqing, China
3
STAT3 Signal Transducer and Activator of Transcription 3 Department of Colorectal Surgery, Harbin Medical University Cancer
STAT5 Signal Transducer and Activator of Transcription 5 Hospital, Harbin, China
4
mPEG2k-DSPE Methoxy Polyethylene Glycol Department of General Surgery, Institute of Precision Diagnosis and
2000-Distearoylphosphatidylethanolamine Treatment of Digestive System Tumors, Carson International Cancer
iRGD Internalizing RGD peptide Center, Shenzhen University General Hospital, Shenzhen University,
IR-780 Near-Infrared Fluorescent Dye Shenzhen 518055, Guangdong, China
5
FGL1 Fibrinogen-Like Protein 1 Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital,
mPEG2k Methoxy Polyethylene Glycol 2000 Fudan University, Shanghai 200032, China
6
ERCC1 Excision Repair Cross-Complementation Group 1 Department of Radiation Oncology, Shandong Cancer Hospital and
c-Myc MYC Proto-Oncogene, BHLH Transcription Factor Institute, Shandong First Medical University, Shandong Academy of
OX40 Tumor Necrosis Factor Receptor Superfamily, Medical Sciences, Jinan 250000, Shandong, China
7
Member 4 (TNFRSF4) Xsphera Biosciences, Translational Medicine Group, 6 Tide Street, Boston,
CpG Cytosine-phosphate-Guanine MA 02210, USA
8
PL1 Phospholipid Nanoparticles 1 Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard
GITR Glucocorticoid-Induced Tumor Necrosis Factor Medical School, Boston, MA 02115, USA
9
Receptor Blood Cell Development and Function Program, Fox Chase Cancer
PLG Poly(lactide-co-glycolide) Center, Philadelphia, PA, USA
10
PLH Poly-L-Histidine School of Public Health, Benedictine University, Lisle, USA
11
IDO Indoleamine 2,3-dioxygenase Department of Urologic Sciences and Vancouver Prostate Centre,
mPEG2k-DSPE Methoxy Polyethylene Glycol University of British Columbia, Vancouver, BC V6H3Z6, Canada
12
2000-Distearoylphosphatidylethanolamine Cumming School of Medicine, Arnie Charbonneau Cancer Research
mPEG2k Methoxy Polyethylene Glycol 2000 Institute, University of Calgary, Calgary, AB T2N 4Z6, Canada
13
ERCC1 Excision Repair Cross-Complementation Group 1 Department of Medical Sciences, University of Calgary, Calgary,
CpG Cytosine-phosphate-Guanine AB T2N 4Z6, Canada
14
PL1 Phospholipid Nanoparticles 1 Present address: NUS Center for Cancer Research (N2CR), Yong Loo Lin
AIEdots Aggregation-Induced Emission dots School of Medicine, National University of Singapore, Singapore
HMGB1 High Mobility Group Box 1 117599, Singapore
15
MART-1 Melan-A Present address: Department of Pharmacology, Yong Loo Lin School of
CCL22 C-C motif chemokine ligand 22 Medicine, National University of Singapore, 16 Medical Drive,
LncRNA Long Non-Coding RNA Singapore 117600, Singapore
16
Laboratory of NF-κB Signalling, Institute of Molecular and Cell Biology
Acknowledgements (IMCB), Agency for Science, Technology and Research (A*STAR), 61
We would like to express our gratitude to Dr. Rupangi Verma from the Biopolis Drive, Proteos, 138673 Singapore, Republic of Singapore
17
Medical and Scientific Communication, Research Support Unit at the National The Graduate School, Augusta University, 30912 Augusta, GA, USA
18
University Health System, Singapore for her meticulous review and editing of Department of Oncology Surgery, Harbin Medical University Cancer
our manuscript for English language accuracy. Hospital, Harbin, China
19
Key Laboratory of Tumor Immunology in Heilongjiang, Harbin, China
Author contributions
Q.L, D.K, S.L and M.A wrote the first draft of paper (Writing original draft). A.R.A, Received: 30 December 2023 / Accepted: 15 March 2024
I.C, Y.T, X.N, Y.W, P.T and L.W critically revised and supervised the paper. G.S,
V.T, F.T, Z.Y and P.H developed the idea and concept and revised the paper
(Writing-review-editing).
Funding References
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Lu et al.

Journal of Hematology & Oncology (2024) 17:16 Journal of Hematology &

REVIEW Open Access

Nanoparticles in tumor microenvironment

This combination of phototherapy and immunotherapy

gens and adjuvants. To address this issue, glycosylated

CD4+ T cell levels, leading to increased infiltration of

An innovative approach in cancer therapy involves

(yeast)-based nanocarriers function as nano-patho-

Increasing immunity by the SIRPα-siRNA

TH17 responses, contributing to anti-cancer immunity

min, can stimulate the maturation of dendritic cells and

tion, but also accelerate the maturation of dendritic cells,

immunotherapy. Lipid nanoparticles delivering anti-

miR-21 have demonstrated the ability to stimulate M1

Nanoparticles have been employed for targeted regu-

lation of immunosuppressive Treg cells in cancer treat-

ment, aiming to enhance immunotherapy potential. For

example, PLGA nanoparticles with antigen-capturing

nanoparticles primarily elevate the CD8+ T cell count,

Treg cells [299]. By augmenting this ratio, the negative

impact of Treg cells on immune responses can be allevi-

ic nanostructures cells 523.9 ± 15 nm and Development of cancer vaccine

function of the immune system [352, 353]. Therefore, tar-

of mature dendritic cells and decreasing MDSCs. Fur-

anti-tumor cytokines [361].

Nanoparticles for delivery of cargo into antigen-presenting

One of the prominent problems in cancer eradication

have opened a new gate for the delivery of immuno-

and even in lack of delivery of cargo, they can stimulate

injection into OVA-expressing melanoma, thymoma, or

cancer immunity [365, 366]. Furthermore, such model

tumors to impair cancer growth and enhance the sur-

and demonstrate high cellular uptake by dendritic cells.

dendritic cell-related MHC class I molecules occurs and

the stimulation of CD8+ T cells is observed [369, 370].

cells Suppression of mitophagy

Biomimetic - - Functionalization of nanoparticles with cancer cell membrane

line HMC3, and

nanocarriers Dendritic cell maturation, TAM depletion and T cell infiltration

the nanoparticles causing PDT and PTT, and their com-

An overview of various classes of nanoparticles in

stimulation of bone marrow-derived dendritic cells and

drugs, genes and vaccines [571]. Until now, multiple

kinds of liposomal nanostructures including 1,2-dioleoyl-

[572, 573] have been significantly applied for the antigen

they can provide cytosol delivery of ovalbumin to accel-

cer progression [576]. Furthermore, loading CpG-ODNs

cific immunity [521]. Micelles are among another kind of

lipid nanoparticles that can function as delivery systems

for antigen/adjuvant to improve potential of vaccines.

delivery of CpG-ODN and Trp2 to create a nanovac-

cine for targeting lymph nodes and enhancing the accu-

mulation of cargo in dendritic cells, triggering CD8+ T

Copper sulphide Melanoma/ 28 nm/30.5 mV Delivery of Cas9 ribonucleoprotein to target PTPN2

phototherapy is recommended to enhance immune

hard to translate to humans. The selection of humanized

Stimulation of PTT to cause immunotherapy

into the clinic. Moreover, the appropriate nanoparticles

FDA U.S. Food and Drug Administration

PARP Poly(ADP-ribose) Polymerase Competing interests