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. 2022 Oct 5;12(10):2258-2279.
doi: 10.1158/2159-8290.CD-22-0504.

Science-Driven Nutritional Interventions for the Prevention and Treatment of Cancer

Léa Montégut  1   2   3 , Rafael de Cabo  4 , Laurence Zitvogel  3   5   6   7   8 , Guido Kroemer  1   2   9
Affiliations

Science-Driven Nutritional Interventions for the Prevention and Treatment of Cancer

Léa Montégut et al. Cancer Discov. .

Abstract

In population studies, dietary patterns clearly influence the development, progression, and therapeutic response of cancers. Nonetheless, interventional dietary trials have had relatively little impact on the prevention and treatment of malignant disease. Standardization of nutritional interventions combined with high-level mode-of-action studies holds the promise of identifying specific entities and pathways endowed with antineoplastic properties. Here, we critically review the effects of caloric restriction and more specific interventions on macro- and micronutrients in preclinical models as well as in clinical studies. We place special emphasis on the prospect of using defined nutrition-relevant molecules to enhance the efficacy of established anticancer treatments.

Significance: The avoidance of intrinsically hypercaloric and toxic diets contributes to the prevention and cure of cancer. In addition, specific diet-induced molecules such as ketone bodies and micronutrients, including specific vitamins, have drug-like effects that are clearly demonstrable in preclinical models, mostly in the context of immunotherapies. Multiple trials are underway to determine the clinical utility of such molecules.

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Figures

Figure 1.
Figure 1.
Anticancer effects of reduced caloric intake. A decrease in caloric intake activates nutrient scarcity signaling pathways and triggers a global metabolic shift—toward catabolism and ketogenesis—as well as an integrated cellular stress response. Cell adaptations to the nutrient restriction-induced stress include autophagy, DNA repair, and antioxidant response at the systemic level. In consequence, circulatory procarcinogenic factors are downregulated: those include inflammatory factors such as IL1β, IL6, and CRP, but also metabolic regulators such as glucose, insulin, insulin growth factor-1 (IGF1), and leptin, which nurture the tumor microenvironment. Finally, calorie-restricted tumors are sensitized to oxidative stress, and autophagy induction favors ATP release, which in turn attracts activate dendritic cells (DCs) into the tumor bed, ultimately stimulating anticancer immune responses by CD8+ T cells. AMPK, AMP-activated protein kinase; EP300, E1A binding protein P300; FA, fatty acids; FGF21, fibroblast growth factor 21; HDL, high-density lipoprotein; HO-1, heme-oxygenase 1; LDL, low-density lipoprotein; mTORC1, mammalian target of rapamycin complex 1; SIRT1, sirtuin 1; SIRT3: sirtuin 3.
Figure 2.
Figure 2.
Anticancer effects of macronutrient-depleting regimens. Protein reduction induces endoplasmic reticulum (ER) stress in cancer cells, thus stimulating the release of C-X-C motif chemokine ligand 10 (CXCL10) and IFNγ. Protein reduction also weakens immunosuppression by tumor-associated macrophages (TAM). The absence of exogenous methionine supply in plant-based diets affects one-carbon metabolism and decreases DNA and histone methylation. The methionine salvage pathway produces polyamines that trigger autophagy. Carbohydrate restriction prevents the noxious effects of addictive sugars, prevents nonalcoholic steatohepatitis (NASH), stabilizes the intestinal barrier, and reduces local and systemic inflammation. At the level of malignant cells, low-carb diet reduces trophic support and sensitizes to oxidative stress. A ketogenic diet cuts off the glucose supply of cancer cells, which, however, can adapt to their metabolism. Ketone bodies such as 3-hydroxybutyrate downregulate immunosuppressive signaling such as C-X-C motif chemokine ligand 12 (CXCL12) secretion and expression of programmed death-ligand 1 (PD-L1) on tumor antigen-presenting cells (APC), enhancing T cell–mediated immunity. DCs, dendritic cells; HMG-CoA, β-Hydroxy β-methylglutaryl-coenzyme A; HO-1, heme-oxygenase 1; OXCT-1, 3-oxoacid CoA-transferase 1; SAH, S-adenosyl-homocysteine; SAM, S-adenosyl-methionine.
Figure 3.
Figure 3.
Anticancer effects of nicotinamide and spermidine. Nicotinamide (NAM) protects against DNA damage and oxidative stress, while it improves cancer immunosurveillance, as indicated by an increase in effector T cells, downregulation of immunosuppressive receptors such as lymphocyte-activation gene 3 (LAG3) and T-cell immunoglobulin and mucin-domain containing-3 (TIM3), upregulated macrophage CD36 and phagocyosis. Spermidine affects arginine, methionine, and acetyl-coenzyme A (Acetyl-CoA), stimulates autophagy, and boosts the immunogenicity of dying cancer cells, thus enhancing cytotoxic and memory T-cell responses. ATP, adenosine triphosphate; CD36, scavenger receptor class B member 3; CD39, ecto-nucleoside triphosphate diphosphohydrolase; DCs, dendritic cells, PARP1, poly(ADP-ribose) polymerase 1; SIRT1, sirtuin 1; TOX, thymocyte selection-associated high mobility group box protein.
Figure 4.
Figure 4.
Microbiota-centered interventions. The microbiota is influenced by interventions on the quantity and quality of macronutrients, such as ketogenic diet, dietary fibers, and polyphenols. Specific bacteria in the gut may have oncoprotective effects on the production of specific metabolites and the stimulation of immunosurveillance, for instance, by the induction of crossreactive immune responses or by stimulation of Toll-like receptor 2 (TLR2). Note that the anticancer effects of Eisenbergiella are still hypothetical as indicated by the question mark. Prot, protein.
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