https://doi.org/10.

1038/d41586-021-02775-1

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for the survival and growth of many types of
cancer, leading to the targeting of glucose
Tumour biology
metabolism as an anticancer thera­peutic

Diet analysis suggests lipid

approach8.
A possible reason for just one of the diets
having an effect on the tumour is that only

imbalance slows cancer the caloric-restriction diet reduced glucose

availability for cells in the tumour. However,
because dietary interventions alter the lev-
els of many metabolite molecules, Lien et al.
Giulia Salvadori & Valter D. Longo
explored whether nutrients other than glu-
Understanding how diet affects tumour growth could lead to cose influenced the anticancer effects of the
better treatments. Analysis in mice reveals that a low-calorie caloric-restriction diet. The authors meas-
ured the availability of fatty-acid molecules
diet, but not a ketogenic diet, slows the growth of pancreatic in the plasma component of blood and in
cancer. This effect is mediated by lipid changes. the tumours. As expected, a ketogenic diet
resulted in high levels of many types of fatty
acid, whereas caloric restriction was associ-
Various diets, such as those that periodi- diets affect the lipids in the blood and tumour. ated with low levels of these fatty acids, raising
cally restrict calorie intake and thereby drive The authors examined mice that had one of the possibility that certain fatty acids support
metabolic changes associated with fasting two types of cancer: pancreatic ductal ade- tumour growth.
(periodic fasting-mimicking diets)1, or ones nocarcinoma or non-small-cell lung cancer. Lien and colleagues show that both diets
that are low in carbohydrates and high in fat Lien et al. assessed the effect of a diet in which reduced the activity of an enzyme called
(ketogenic diets), are emerging as nutritional a 40% reduction in caloric consumption was stearoyl-­CoA desaturase (SCD), which helps to
interventions that can delay cancer growth achieved by lowering carbohydrate intake; produce monounsaturated fatty acids (those
and perhaps boost the effect of anticancer they also evaluated the effects of a ketogenic with one carbon–carbon double bond) from
drugs1,2. Whereas long-term calorie restric- diet consisting of a normal level of calories but saturated fatty acids (those that lack c­ arbon–
tion is not feasible for people on most cancer made up of an intake of 90% fat, 9% protein carbon double bonds). SCD is needed for
therapies because it leads to weight loss and and 1% carbohydrates. The authors found that cancer cells to proliferate in a lipid-depleted
lean body mass3, ketogenic diets and periodic the low-calorie diet reduced tumour growth environment, as reported by the authors. How-
fasting-mimicking diets are beginning to be in these models, but the ketogenic diet did ever, only the caloric-­restriction diet reduced
tested in a series of clinical trials, and are par- not, even though both diets led to a similar the levels of monounsaturated fatty acids and
ticularly promising when used in combina- decrease in blood-glucose levels. Glucose affected the ratio of unsaturated to saturated
tion with standard therapies1,2,4–6. Writing in levels have been reported to be fundamental fats, suggesting that an imbalance between
Nature, Lien et al.7 fill in some of the missing
details about how diet affects cancer growth.
Animal studies provide evidence suggest- a Caloric-restriction diet b Ketogenic diet
ing that various dietary interventions can be
potent in combination with standard anti­
cancer drugs4. But the results also underline
the importance of both the relative levels of ↓ Glucose, ↓ Activity of ↓ Lipids ↓ Insulin ↓ SCD ↑ Lipids
calories, proteins, fats and carbohydrates amino acids SCD enzyme activity
and insulin
in a diet, and the duration and frequency of ↓ Fatty acids ↓ Activity ↑ Fatty acids
the diet’s administration. What makes the SFA of the PI3K
↓ Activity pathway
implementation of certain diets in the clinic SCD
of the TOR, ↓ MUFAs Normal level
even more complex is that they can be highly AC and PI3K MUFA Altered of MUFA
effective in combination with one drug, but pathways MUFA:SFA Normal
ineffective with another. Thus, understanding ratio MUFA:SFA ratio

the molecular mechanisms that enable dietary

Slowing of tumour growth Diet is less effective
interventions to result in toxicity to cancer than caloric-restriction diet
cells, or to increase the effectiveness of stand- for slowing tumour growth
ard drugs, is essential to the development of
standard-of-care (treatments routinely recom-
Figure 1 | How diet affects tumour growth in mice. a, A low-calorie diet slows tumour growth by lowering
mended by clinicians) cancer therapies that glucose, amino acids and the hormone insulin and thereby inhibiting various tumour-promoting signalling
include a dietary component. pathways (the TOR, AC and PI3K pathways)4. Lien et al.7 report that this diet also inhibits the enzyme SCD,
Lien and colleagues’ study contributes which can convert a saturated fatty acid (SFA) to a monounsaturated fatty acid (MUFA). The perturbed
molecular insights (Fig. 1) into how the effec- balance of fatty acids slows the growth of pancreatic tumours. b, A ketogenic diet, high in fat but of normal
tiveness of different diets in slowing the calorie content, also influences the insulin pathway as Lien et al. report. However, it does not alter the
growth of various cancers depends on how the SFA:MUFA ratio, and it enables pancreatic tumours to grow.

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News & views
these types of fatty acid affects tumour growth. calorie restriction or the more-restrictive Giulia Salvadori and Valter D. Longo are
The authors carried out experiments to test fasting mimicking diets (periodic cycles of at the IFOM, FIRC Institute of Molecular
this hypothesis, and found that increasing the a diet able to mimic the metabolic changes Oncology, Milan 20139, Italy. G.S. is also in
activity of SCD partially blocked the slowing induced by water-only fasting) are effective the Department of Oncology and Hemato-
of tumour growth caused by caloric restric- against a wide range of cancers because they oncology, University of Milan. V.D.L. is also in
tion. When the authors examined the profile each reduce levels of several factors, including the Longevity Institute and Davis School of
of fatty acids in SCD-expressing tumours, they glucose and the proteins insulin, IGF-1, leptin Gerontology, University of Southern California,
observed a higher ratio of monounsaturated and ferritin, moreover, they also alter the avail- Los Angeles, California, USA.
to saturated fatty acids than was evident in the ability of amino acids and fats9–11. e-mail: [email protected]
mice on a caloric-restriction diet. Although it is important to identify dietary
To test their proposed mechanism for how changes that alone can delay tumour growth,
caloric restriction mediates the inhibition of it will be crucial to establish combinations of
pancreatic tumour growth, Lien et al. gave wide-acting dietary restrictions and targeted
1. de Groot, S. et al. Nature Commun. 11, 3083 (2020).
mice a high-fat, caloric-restricted diet rich drugs that are highly effective against various 2. Zahra, A. et al. Radiat. Res. 187, 743–754 (2017).
in palm oil to restore the ratio of unsaturated cancers. Indeed, it was previously shown in 3. Dirks, A. J. & Leeuwenburgh, C. Mech Ageing Dev. 127, 1–7
to saturated fats back to that of mice on a mice12 that cycles of fasting act similarly to the (2006).
4. Nencioni, A., Caffa, I., Cortellino, S. & Longo, V. D. Nature
normal diet. The authors report that this par- chemotherapy drug gemcitabine in delaying Rev. Cancer 18, 707–719 (2018).
tially blocked the effect of caloric restriction the growth of pancreatic tumours in mice, but 5. Hopkins, B. D. et al. Nature 560, 499–503 (2018).
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(2015).
caloric-restriction diet was effective against citabine had a strong effect in inhibiting the 7. Lien, E. C. et al. Nature https://doi.org/10.1038/s41586-021-
pancreatic and lung cancer, the addition of progression of pancreatic cancer. 04049-2 (2021).
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9. Lee, C. et al. Sci. Transl. Med. 4, 124ra27 (2012).
growth only in pancreatic cancer. This finding on how low-calorie but not ketogenic diets can 10. Caffa, I. et al. Nature 583, 620–624 (2020).
underlines the need to focus both on therapies impair the growth of specific tumours, paving 11. Di Tano, M. et al. Nature Commun. 11, 2332 (2020).
targeted to specific cancers and on wide-acting the way for further work aimed at evaluating 12. D’Aronzo, M. et al. Oncotarget 6, 18545–18457 (2015).

dietary interventions that together have con- the involvement of other metabolites in the V.D.L. declares competing interests. See go.nature.
sistent antitumour effects. Indeed, long-term survival of cancer cells. com/3irvsId for details.

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