Cancer cells acquire distinct metabolic preferences based on their tissue of origin, genetic alterations and degree of interaction with systemic hormones and metabolites. These adaptations support the increased nutrient demand required for increased growth and proliferation. Diet is the major source of nutrients for tumours, yet dietary interventions lack robust evidence and are rarely prescribed by clinicians for the treatment of cancer. Well-controlled diet studies in patients with cancer are rare, and existing studies have been limited by nonspecific enrolment criteria that inappropriately grouped together subjects with disparate tumour and host metabolic profiles. This imprecision may have masked the efficacy of the intervention for appropriate candidates. Here, we review the metabolic alterations and key vulnerabilities that occur across multiple types of cancer. We describe how these vulnerabilities could potentially be targeted using dietary therapies including energy or macronutrient restriction and intermittent fasting regimens. We also discuss recent trials that highlight how dietary strategies may be combined with pharmacological therapies to treat some cancers, potentially ushering a path towards precision nutrition for cancer.
Diet plays a role in virtually all aspects of cancer including tumour initiation, progression and response to treatment. For example, estimates suggest that up to one-third of the most common cancers are preventable, in part, through dietary modification1,2,3. These associations were established using large-scale population-based observational cohort studies, which provide valuable information about correlations but cannot assess causation and suffer from the notorious difficulty of accurately recording dietary intake4,5. Controlled, mechanistic studies in preclinical models have greatly improved our understanding of how tissues utilize nutrients and the impact diet may play in tumour initiation, progression and treatment response. These studies have shown that diet can supply the tumour with nutrients such as sugars and lipids that can be used for tumour growth6; modulate systemic hormones such as leptin, insulin, insulin-like growth factor 1 (IGF1) and oestradiol that promote tumour cell proliferation and survival7,8; and support the development of obesity, which creates a milieu that favours tumour initiation and progression8. As the links between dietary factors and tumour initiation have been well reviewed and summarized elsewhere9,10,11, our focus in this Review is the impact of diet on tumour progression and how this information is being translated into anticancer therapy.
We are on the precipice of a revolution in the way we treat patients with cancer. Several rigorous preclinical studies in mice, such as those by Hopkins et al., Caffa et al. and Maddocks et al., have shown that dietary interventions enhance anticancer therapy and improve cancer outcomes12,13,14. The translation of these findings is well underway with early-phase clinical data supporting their feasibility and safety15,16. Over the next 5 years, randomized controlled trials will be conducted to establish the importance of diet on clinical outcomes in patients with cancer. In this Review, we describe the key genetic and metabolic features of tumours and their host tissues that should make them vulnerable to dietary interventions. We assess the state of the field and offer suggestions on how to make precision nutrition a reality for cancer treatment.
Metabolic vulnerabilities of cancer
General pathways of nutrient metabolism
The reprogramming of cell metabolism is a hallmark of cancer17. Transformed cells adapt to a state of unregulated cell growth and proliferation by upregulating nutrient uptake and anabolic processes (Fig. 1). Sugars, amino acids and fats are the basic dietary nutrients that support the growth of cancer cells.
Glucose, the most extensively studied nutrient in cancer biology, is a primary energy source for cells and is obtained from the digestion of dietary carbohydrates or generated de novo by anabolic processes in the liver or kidney. Once imported via glucose transporters, glucose can be metabolized in cells in two main ways. The first and ancestrally older path is glycolysis. Glycolysis takes place in the cytosol and breaks down glucose to yield ATP, reducing equivalents, such as NADH, and pyruvate. The second, oxidative phosphorylation, uses energy from the oxidation of reducing equivalents to create an electromotive force across the mitochondrial inner membrane, reducing and consuming oxygen in the process. This potential difference dissipates through ATP synthase to generate ATP. Oxidative phosphorylation is a more efficient way to generate ATP per unit of glucose as compared with glycolysis, but less efficient than glycolysis when considered per unit of oxygen18.
The vast majority of ATP comes from the coupling of glycolysis with oxidative phosphorylation but this link is perturbed in two scenarios. The first is hypoxia, where oxygen becomes limiting and the final electron transfer of oxidative phosphorylation is halted. Hypoxic cells upregulate glycolysis to generate ATP and reduce the overflow of NADH18. The second scenario occurs in certain rapidly proliferating cells such as T cells, embryonic stem cells and tumour cells19,20,21. Here, regardless of oxygen levels, cells typically exhibit high rates of glycolysis and lactic fermentation. Lactate was long thought to be a mere waste product of glycolysis, but is now recognized as an important fuel source for human tumours and healthy tissues22,23,24. In fact, stable isotope tracing studies in fasted mice reveal that lactate incorporation into tricarboxylic acid (TCA) cycle intermediates surpasses that of glucose in all tissues except the brain24,25.
In addition to glucose and lactate, fructose also plays an important role in the metabolism of many different tissues. Although the small intestine and liver see the largest concentrations of dietary fructose, serum fructose rises significantly after fructose consumption and is metabolized by tissues such as the kidney, prostate and bone marrow26,27,28,29. Inside the cell, fructose can be cleaved into glycolytic intermediates and oxidized for energy production. Despite using many similar pathways to glucose, fructose metabolism is uniquely regulated and often results in different downstream end points30. Studies in mice suggest that fructose can reprogramme metabolic pathways for anabolic metabolism and cell survival31, a role that may be particularly important in solid tumours32,33,34.
Other nutrients such as amino acids serve as building blocks for anabolic processes. Glutamine is a non-essential amino acid arising from dietary sources, muscle degradation or de novo synthesis pathways. Via its conversion to α-ketoglutarate, glutamine provides carbon for TCA cycle intermediates that can then be siphoned off for various anabolic processes such as the synthesis of fatty acids35. In contrast to glutamine, the branched-chain amino acids (BCAAs) (leucine, isoleucine and valine) are essential amino acids primarily obtained from dietary sources. Studies in mice show that these can be taken up by many tissues and tumours to be incorporated into newly synthesized proteins or oxidized for fuel36,37.
Fatty acids are a dense source of energy that can be obtained from the diet and stored in the body as triglycerides. In times of low food intake, mammals catabolize triglycerides and release the resulting fatty acids and glycerol. Glycerol can be used by cells as a glycolytic, gluconeogenic or lipogenic substrate. Fatty acids can be oxidized to generate ATP, reused in the synthesis of other lipid moieties such as phospholipids and cholesterol esters or stored in intracellular lipid droplets. When oxidized by the liver, fatty acids generate ketone bodies, which are released into circulation and fed into the TCA cycle in certain tissues25. These processes are frequently upregulated in rapidly proliferating tissues such as tumours38,39,40.
Cancer cells acquire distinct metabolic preferences based on their tissue of origin, genetic alterations and degree of interaction with systemic hormones and metabolites. The tissue of origin has a particularly strong effect on metabolite abundance and metabolic gene expression in tumours owing to engrained, lineage-dependent preferences for sugars, fats and amino acids41,42,43,44 (Fig. 2). For the sake of brevity, this Review focuses on the metabolism of a subset of tissues that have a high predilection for malignant transformation as well as strong literature supporting a relationship with dietary nutrients. For the interested reader, excellent reviews are available summarizing what is known about how diet and tumour metabolism relate in other cancer types, for example gastric and kidney cancers45,46.
The brain is a unique organ that depends on the uptake and oxidation of glucose and/or ketone bodies and is also separated from systemic circulation by the selectively permeable blood–brain barrier. High glucose utilization is driven, in part, by expression of the gene encoding the transporter solute carrier family 2 member 3 (SLC2A3), which has a high affinity and transport capacity for glucose47. Interestingly, mouse studies reveal that there is marked heterogeneity in glucose uptake within different regions of the brain48. Furthermore, a large body of evidence including tracer imaging studies in mice and humans indicates that neurons may prefer to use lactate generated by local astrocytes as a primary fuel49. Mouse and rat studies suggest that the brain is also capable of metabolizing ketone bodies during fasting, although the uptake and usage is also spatially heterogeneous50,51,52. Fatty acids, meanwhile, are seldom used by neuronal cells to meet energetic demands25,53. Similarly, amino acids such as glutamine are rarely oxidized by brain cells25. Glutamate is an excitatory neurotransmitter than can cause neurotoxicity if it accumulates, so it is rapidly converted to glutamine by astrocytes and then transported back to neurons49.
Primary brain tumours adapt metabolically to grow and survive. For example, many brain tumours express higher levels or different isoforms of glycolytic enzymes (for example, hexokinase, pyruvate kinase, pyruvate dehydrogenase (PDH)), which provide them with specific advantages in the brain’s unique environment (reviewed in detail elsewhere49). Some of these unique features may be exploited for therapy or diagnosis. For example, in vitro studies indicate that depriving brain tumours of glucose may be a useful therapeutic strategy as normal neurons, but not glioma cells, are capable of surviving on ketone bodies54. A subset of particularly aggressive brain tumours promote glycolysis by downregulating the mitochondrial pyruvate transporter subunit MPC1, which makes cells dependent upon glutamine uptake in vitro49,55,56. Mutations in isocitrate dehydrogenase (IDH1 or IDH2) occur in 70% of intermediate-grade gliomas and affect glioma sensitivity to nutrient deprivation57; in vitro tracing studies suggest that these tumours particularly depend on glutamine58,59,60 (Fig. 1).
Nutrient availability also appears to affect the growth of metastatic tumours within the brain. For example, the brain has relatively low availability of serine and fatty acids relative to serum, and mouse models indicate that breast cancer metastases to the brain have increased reliance on de novo generation of these components61,62. Furthermore, nuclear magnetic resonance (NMR) labelling studies of resected human tumours reveal that metastases from a wide variety of primary sites can acquire the ability to oxidize acetate as a fuel source when they arrive in the brain63.
Mammary glands within breast tissue have a high capacity to synthesize large amounts of macromolecules, which get exported into milk. The substrates for this process are diet-derived and include glucose, fatty acids, lipoproteins and amino acids (especially methionine)64. Much nutrient uptake by the breast is regulated by insulin, IGF1 and steroid hormones such as oestrogens and progesterone. For example, fluorodeoxyglucose (FDG) uptake in human breast tissue increases with progesterone levels, and uptake and production of lipids and proteins are strongly regulated by insulin65,66,67,68.
Dysregulation of the pathways involved in hormone sensing and nutrient uptake in the breast can promote cancer development. For example, the PI3K pathway is typically hyperactivated in human breast tumours via mutations in the gene for the main catalytic subunit, PIK3CA (ref.69). PI3K is a lipid kinase that responds to environmental growth signals such as insulin and IGF1 to promote proliferation and nutrient uptake70. Studies with patient-derived cell lines show that hyperactivation of PI3K is one way that oestrogen receptor (ER)-positive tumours may evade hormonal therapy71. Correspondingly, data from mouse models and humans treated with PI3K inhibitors show that tumours upregulate ER signalling as an escape strategy72. These findings have prompted clinicians to begin targeting both PI3K and ER — an approach that is proving effective in some patients with breast cancer73.
The molecular features of breast tumours impact nutrient uptake and metabolism. Human imaging studies corroborate preclinical models showing that ER-positive tumours are relatively oxidative and consume lactate and citrate, whereas triple-negative breast tumours are more glycolytic lactate exporters74. The expression of oestrogen-related receptors (ERRs), orphan nuclear receptors with structural similarity to ER, can also change breast tumour metabolism. For example, human genomic studies and in vitro models indicate that ERRα activity promotes the expression of myriad metabolic enzymes and confers an aggressive glycolytic phenotype with a worse prognosis75. Human genomic studies and xenograft mouse models also show that triple-negative breast tumours depend on de novo synthesis of serine, which is limiting in the tumour microenvironment and can be further depleted via diet76,77,78.
Fatty acid metabolism also appears important for the development of certain molecular subtypes of breast cancer. For example, compared against breast tissue from healthy women, normal tissue from women who later developed cancer showed upregulated fatty acid uptake and transport, lipolysis, lipid peroxidation and epithelium–adipose tissue crosstalk79. Uptake of exogenous fatty acids portends a worse prognosis and is typical of aggressive, triple-negative tumours80. Fatty acid metabolism may also be perturbed in local adipose deposits in the breast. In vitro co-culture studies show that adipocytes can deliver fatty acids to tumour cells and induce gene expression changes that enhance tumour cell migration81,82. Adipocytes also generate oestrogen via aromatase, which may explain why oestrogen levels are much higher in benign human breast tissue and tumours than in serum83.
Similar to the breast, the endometrium is a hormone-responsive tissue with high fluctuations in metabolic demand. Studies from mouse and human endometrial stromal cells show that glucose transporter expression and glucose uptake are positively regulated by progesterone and negatively regulated by oestrogen84. Moreover, insulin stimulates the growth of the endometrial mucosa, especially in the proliferative phase of the endometrial cycle where IGF1 signalling is essential85. In mouse models, cell-autonomous activation of the PI3K pathway is sufficient for the initiation of endometrial tumours86, and the PI3K pathway is frequently activated in human endometrial carcinoma6,87. More than 90% of human endometrial tumours have genetic alterations in the PI3K signalling pathway, often by activating mutations in PIK3CA, or loss-of-function mutations in PTEN, the gene encoding a phosphatase that directly opposes PI3K (refs6,87). These alterations likely underlie the clinical associations of endometrial cancer with biomarkers of hyperinsulinemia such as fasting glucose, insulin, c-peptide (insulin production), haemoglobin A1C (chronic hyperglycaemia) and dietary glycaemic load6.
As with the breast and endometrium, the prostate is highly sensitive to sex hormones. In particular, testosterone drives glucose uptake, which can be detected via FDG-PET and reversed with oestrogen administration in rats88. In vitro and mouse models also show that testosterone significantly accelerates incorporation of amino acids into protein and of acetate into fatty acids and citric acid89. These changes help support the primary biosynthetic role of the prostate to produce seminal fluid, which is rich in citric acid and hydrolytic enzymes arising from specialized epithelial cells. These cells are highly glycolytic and have diminished capacity for oxidative phosphorylation to enable them to generate and export citrate90. Seminal fluid is also rich in fructose, and studies from human tissue suggest that this fructose is generated de novo from glucose via the polyol pathway91. This pathway uses aldose reductase to reduce glucose to sorbitol, and then sorbitol dehydrogenase (SDH) that oxidizes sorbitol to fructose (Fig. 1). Interestingly, SDH is an androgen-regulated gene that is expressed in benign and malignant human prostate cancers, in addition to the seminal vesicles92.
As with most other tumour types, cancerous transformation increases nutrient uptake and utilization in prostate cancer. Interestingly, mouse and human tissue studies show that prostate cancer cells regain the ability to perform oxidative phosphorylation during transformation90. This adaptation allows these tumours to readily consume and oxidize locally produced nutrients such as citrate and lactate74,90. Moreover, emerging evidence suggests that fructose can be a key substrate for prostate cancer cells. For example, human primary prostate tumours have high expression of SLC2A5, the main fructose transporter28. Fructose may arise from dietary sources or the tumours may gain access to fructose-dense fluid during seminal vesicle invasion, which confers a worse prognosis in humans even above other local invasion93,94. Fatty acids may also be important for prostate cancers, as suppressing their uptake slows tumour progression in mouse models95,96.
Stable isotope labelling studies in healthy pigs show that lung metabolism is notable for relatively high consumption of hydroxybutyrate and acetoacetate (ketone bodies), glutamine and saturated fatty acids97. Nutrient uptake in the lung is not particularly sensitive to systemic hormones. For example, there are minimal changes in the contribution of glucose and lactate to TCA cycle intermediates with fasting and refeeding, as compared with other tissues25.
The lung is an excellent example of a tissue where local effects likely alter tumour metabolic phenotypes. As in many other tumours, mutations in primary lung tumours occur in pathways that are associated with increased glucose uptake and flux to anabolic pathways. These mutations include genes in the epidermal growth factor receptor (EGFR)–PI3K pathway, oncogenes such as KRAS and MYC, and tumour suppressor genes such as STK11 (ref.98). However, lung tumours with these alterations often have different metabolic phenotypes compared with genetically similar tumours in other tissues. This distinction may be due to the unique features of the lung environment, which offer a set of metabolic advantages to primary and metastatic tumours alike. For example, studies in mouse models show that the lung environment may better allow pyruvate and proline metabolism and, thereby, preferentially support breast cancer metastasis99,100. Another example comes from in-human stable-isotope tracing studies that found that non-small-cell lung cancer (NSCLC) tumours maintain high levels of glucose oxidation and can use a wide variety of TCA substrates including, possibly, lactate101. In this study, tumour metabolism was highly heterogeneous between and within tumours, suggesting that variations in the tumour environment within the same tissue also alter metabolism101. A final illustration of the tumour site altering the metabolic phenotype comes from mouse studies that show that KRAS-mutant pancreatic tumours avidly scavenge their microenvironment for nutrients via macropinocytosis, but KRAS-mutant NSCLC tumours take up comparatively less — even when derived within the same organism37,102.
Some metabolic features of lung tumours may prove to be metabolic vulnerabilities. For example, human lung tumours express high levels of fructolytic enzymes relative to normal lung tissue, and inhibiting fructose uptake reduces tumour growth in xenograft models34. Glutamine dependence has also been reported in some preclinical KRAS-driven tumour studies, with cells carrying KRAS-G12V being less dependent on glutamine than cells expressing KRAS-G12(C/D) (ref.103). However, other studies in mouse models suggest that glutamine metabolism is dispensable for fuelling the TCA cycle when glucose is present104,105. KRAS-mutated tumours may also be sensitive to therapies targeting BCAA and fatty acid metabolism. BCAA uptake is elevated in NSCLC tumours versus normal lung, consistent with low serum levels early in clinical disease, and deletion of the BCAA transporter impairs tumour formation in mice37,106. Fatty acid metabolism may also be a promising target, and at least one enzyme, acyl-coenzyme A synthetase long-chain family member 3 (ACSL3), is highly expressed in human NSCLC and is essential for KRAS-mutant lung cancer tumorigenesis in mice107.
The primary role of the pancreas is anabolic: to synthesize and secrete hormones and enzymes. This process requires a large influx of amino acids, which serve as both building blocks for protein synthesis and fuel for TCA cycle-dependent amino acid production. Out of 11 organs thoroughly profiled in mice and pigs, the pancreas shows the greatest use of amino acids25,97. These amino acids are consumed and repurposed by zymogen-producing acinar cells25,36.
Despite its role as a major endocrine organ and exposure to high levels of insulin, the uptake of nutrients by the pancreas is not particularly sensitive to systemic hormones. In fact, insulin-mediated glucose uptake contributes little to TCA intermediates in mouse pancreas. Instead, fatty acids and ketone bodies are used more readily, especially in times of fasting25. Despite these findings, systemic insulin has been shown to promote the formation of precancerous lesions in the mouse pancreas108. These data suggest that the role of insulin in pancreas tumorigenesis may be independent of its ability to stimulate glucose uptake.
Mutations in KRAS are common in human pancreatic ductal adenocarcinomas (PDACs), and these tumours have several familiar and several unique metabolic features that may prove to be targetable vulnerabilities. For example, in vitro labelling and mouse tumour genetic analyses indicate enhanced glucose uptake, flux through glycolysis and diversion of carbon into the hexosamine and pentose phosphate pathways in these tumours109. However, studies in KRAS-driven PDAC cells and mouse models show that these tumours have increased reliance on glutamine anapleurosis through a non-canonical enzymatic pathway110. Also, in an apparent exception to the trend of tumours sharing metabolic preferences with their tissue origins, BCAA consumption is decreased in PDACs relative to normal pancreas in mice37,106. In vitro and mouse studies suggest that KRAS-driven PDAC cells rely on scavenging extracellular amino acids via macropinocytosis, in contrast to KRAS-driven tumours of the lung, as discussed above37,102,111,112. Mouse models and epidemiological data also suggest that fatty acid uptake from the serum is an important feature of PDAC and pre-malignant cells in the pancreas. For example, in vitro lipid labelling studies as well as gene expression analysis of mouse tumours show that RAS-transformed pancreatic cells avidly consume unsaturated fatty acids from their environment, potentially as a way to circumvent hypoxia-induced inhibition of stearoyl-CoA desaturase (SCD)113,114. Dietary interventions limiting unsaturated fatty acid availability slow tumour growth in mice bearing PDAC allografts, and may be viable therapeutic options in humans115.
The intestinal epithelium is exposed to large, periodic fluctuations in nutrients based on the quantity of food intake and the activity of resident microbiota. Traditionally, the intestine has been seen as mainly a transporter of dietary nutrients, but recent work has highlighted its more active role in metabolism. For example, the mouse intestinal epithelium converts low doses of dietary fructose into glucose and organic acids that are subsequently delivered to the portal blood and liver27. In vivo labelling studies in mice and pigs also show that the intestines are the primary site for production of the body’s short-chain fatty acids such as propionate, butyrate and acetate, which are mainly generated by gut microbiota97,116. In addition to producing nutrients for the body, the intestines consume circulating nutrients such as glucose and glutamine. In fact, mouse and porcine labelling studies also show that the small intestine is one of the primary sites of glucose disposal in the fed state and of ketone body oxidation while fasting25,97.
Colorectal cancer (CRC) is the most common cancer arising from the intestine, and its metabolism reflects its driving mutations, nutrient availability and tissue of origin. Most CRCs arise from sporadic mutations in the WNT, PI3K and KRAS pathways13,14,15. WNT signalling is hyperactive in 93% of CRC tumours and is associated with impaired oxidative metabolism, increased pentose-phosphate pathway (PPP) flux and increased fatty acid synthesis in in vitro studies, mouse xenograft models and human tumour samples117,118. PI3K pathway mutations confer a dependence upon glutamine uptake and metabolism, which have been effectively targeted to reduce tumour growth in mouse models119,120. KRAS mutations confer enhanced glucose transporter expression and improved cell survival in low-glucose conditions in human CRC-derived cell lines and mouse xenograft tumours121. Emerging evidence suggests that CRC tumours can also directly transport and metabolize fructose from the diet: consumption of moderate amounts of fructose enhances intestinal tumour growth in mice by amplifying the expression of hypoxia response genes. Fructose’s effect on tumour growth can be negated by targeting the fructolytic enzyme, ketohexokinase (KHK), or the glycolytic enzyme pyruvate kinase isoform M2 (PKM2), which plays a critical role in mediating hypoxia signalling122,123.
The pancreas and intestines drain into a pool of venous blood that is directly filtered and sampled by the liver. This unique anatomy makes the liver a nutrient-rich and growth factor-rich environment ideal for metastatic growth and tumorigenesis. For example, the liver is exposed to high levels of fructose, lactate and organic acids from the small intestine, and insulin from the pancreas, as compared with other tissues25,27,116. The liver is also hormone-sensitive, and studies of the transcriptional profile of mouse livers over time show high rates of uptake and production of various metabolites depending on circulating hormones as well as cell-intrinsic circadian signals124. For example, stable isotope labelling studies in pigs show that the liver takes up circulating fatty acids (primarily unsaturated), amino acids and lactate, and releases glutamate and ketone bodies in response to the low insulin and high glucagon state induced by fasting97. The liver is also one of the few tissues capable of generating and releasing glucose via gluconeogenesis and is the main source of circulating glucose in fasted mice25.
Hepatocellular carcinoma (HCC) is the most common primary tumour in the liver, and its development and progression are closely related to nutrient intake and systemic metabolism. HCC typically evolves gradually from chronically diseased liver tissue such as in the setting of non-alcoholic fatty liver disease (NAFLD), which is estimated to affect up to one-third of the adult population globally125. As a result, much attention has been paid to the systemic and local metabolic alterations contributing to the development of NAFLD and its progression to HCC. For example, epidemiological studies in the past two decades have shown that obesity and the metabolic syndrome confer an increased risk of NAFLD and its progression to HCC126. Diets associated with obesity such as those high in both fat and fructose also promote HCC in chemically induced mouse models127,128. Mechanistically, de novo lipogenesis (DNL) is purported to play an important role in the progression from NAFLD to HCC. The exact sequence of events linking DNL and HCC is still debated, although one theory posits that increased uptake and generation of lipids by hepatocytes contribute to a setting of chronic liver inflammation that selects for progenitor HCC cells125,129. Indeed, a recent study showed that rats with an activating mutation in the de novo lipogenic enzyme, acetyl-CoA carboxylase (ACC), when fed a high-fructose diet, exhibited increased hepatic carcinogenesis as well as tumour cell proliferation. Moreover, an ACC inhibitor effectively reduced tumour proliferation in the rats and in human tumour-derived cell lines130. One substrate that HCCs use for lipogenesis is glucose, and similar to other cancers, HCCs generally upregulate glycolysis, although human imaging studies show that glucose uptake is highly variable and certain tumours prefer to use alternative nutrient sources such as acetate131,132.
In addition to the typical macronutrients studied in the context of other tumours, the intestine and liver have unique exposures to dietary, microbial and gastrointestinal-secretory products that must be considered. For example, mouse studies reveal that high-fat diets can promote microbiota species that increase the amount of tumour-promoting bile acid species in the intestine133. Additional studies in germ-free versus conventionally housed mice reveal that the short-chain fatty acid butyrate, produced by microbial metabolism of dietary carbohydrate in the intestine, is a major energy source for differentiated colonocytes134. Although butyrate production can be modulated by dietary interventions, existing mouse studies offer conflicting indications about whether such interventions would be desirable therapies for CRC, and more studies are needed135,136. Microbial short-chain fatty acids are also important substrates for the liver. For example, recent tracing studies in mice reveal that dietary fructose serves as both a signal and a substrate for hepatic lipogenesis, in part through its conversion to acetate by gut-resident microbiota116. Global gene expression profiling of human HCCs also identified a subset of aggressive tumours that may rely on gut-derived acetate for fatty acid synthesis, presenting a promising population for dietary and/or microbial interventions137. Beyond these few examples of microbial-influenced nutrient availability for tumours, there are a plethora of studies available in preclinical models reporting associations between the microbiome and cancer initiation, growth and response to therapy, which are covered in excellent reviews elsewhere138. Because elements of the microbiome are clearly influenced by diet, such mechanistic associations between the microbiome and cancer present attractive targets for dietary interventions in human studies.
Systemic effects of dietary therapies
Dietary interventions could potentially improve tumour therapy in several ways. For example, diets can eliminate specific nutrients that tumours use as fuel. They can also potentiate other forms of therapy, such as radiotherapy (Box 1) and chemotherapy, by depriving tumours of escape nutrients and signals. Diets can also act secondarily, modulating the abundance of growth factors or altering the systemic immune state to affect tumour growth and the antitumour immune response, respectively10.
Dietary interventions come in various forms139. Some focus on content, such as energy (caloric) restriction or macronutrient manipulation, whereas others are defined by timing, such as intermittent fasting regimens that impart intervals of complete or partial energy restriction, regardless of meal composition. As these interventions have long been utilized in the fields of obesity and diabetes, we include a brief review of these studies to help identify the potentially beneficial metabolic responses that may occur in patients with cancer. For example, studies in subjects with obesity have shown that any dietary intervention with a caloric deficiency will activate a neurohormonal response leading to weight loss, a decrease in insulin and leptin levels, activation of lipolysis in adipose tissue and reduced blood glucose variability139.
Calorie restriction reduces the total daily energy intake while maintaining a well-balanced macronutrient ratio. In most clinical applications, subjects reduce their caloric intake by 15–30%. This amount of calorie restriction lowers body weight, fat mass, insulin, thyroid hormones and the metabolic rate in adults with overweight140,141,142. These findings persist at 6 months and 2 years of intervention141,143, and also occur in subjects with obesity with pre-existing metabolic dysfunction144,145. In studies of calorie restriction, dropout rates of 30–40% can be achieved when all foods are provided and participants are highly motivated146,147. Calorie restriction is typically well tolerated with few unexpected adverse events148.
Since the early 1900s, researchers have observed the beneficial effects of calorie restriction in mouse tumour models149. In addition to reducing tumour incidence in mice, calorie restriction slows the progression of cancer and the incidence of metastasis150. For example, calorie restriction provides greater protection against established breast and intestinal tumour growth and metastasis151,152. The mechanism by which calorie restriction could improve tumour outcomes is pleotropic. Calorie restriction reduces insulin, which lowers tumour PI3K signalling153. Calorie restriction also promotes beneficial changes in the immune signature151, activation of antioxidant pathways154 and beneficial reductions in circulating unsaturated fats115.
There are limited human data describing the effects of calorie restriction as an anticancer intervention148. Short-term studies show that it does not increase grade 3 or 4 adverse events during chemotherapy, suggesting calorie restriction is safe155,156. In 2007, a phase III trial was initiated to test the effect of calorie restriction and exercise (administered as the Diabetes Prevention Program) on disease-free survival and overall survival in postmenopausal women with breast cancer. Unfortunately, the accrual was terminated early owing to loss of funding and only 338 of the planned 2,150 women were enrolled. The available data were promising, showing a small (~4%) but significant weight loss at 2 years with only a 22% dropout rate and a trend towards improved disease-free survival (hazard ratio 0.71, 95% confidence interval 0.41–1.24, P = 0.23)157,158. Therefore, we eagerly await the results of the Breast Cancer WEight Loss Study (BWEL Study), a randomized phase III trial evaluating calorie restriction as an adjuvant treatment for early breast cancer159.
Fasting mimicking diets
During calorie restriction interventions, the period of fasting between meals is a commonly ignored confounding variable. Mice undergoing calorie restriction will consolidate food intake into a single meal leading to an intermittent, large influx of calories spaced by long periods of fasting and hyperactivity160. This adaptation has led some to question whether it is the calorie restriction, per se, or the fasting period that mediates the benefits of calorie restriction in mouse models. In carefully controlled studies in mice comparing calorie restriction with fasting interventions that provide a normal amount of calories in one meal per day, fasting results in similar improvements in health and survival, regardless of caloric intake, diet composition and bodyweight161,162.
In small clinical studies of subjects with cancer undergoing chemotherapy, fasting lowered pro-tumorigenic hormones, reduced adverse events and improved quality of life163,164. Fasting also alters the abundance of peripheral immune cells such as monocytes and a subset of dendritic cells, which may have beneficial antitumour effects165. However, prolonged periods of fasting are hard to maintain166. Therefore, several regimens of intermittent fasting have been designed to mimic the benefits of fasting and improve long-term adherence167. One such programme is the fasting mimicking diet (FMD) where subjects undergo cycles of consuming calorie-restricted, low-carbohydrate, low-protein diets for four or five consecutive days each month. For example, FMD may consist of a 5-day, plant-based diet comprising up to 600 calories on day 1 and up to 300 calories on days 2–5 (ref.16). The food is not restricted during the remainder of the month, so participants get a long break between FMD cycles. In a randomized crossover study of 100 healthy subjects, 3 FMD cycles reduced body weight and total body fat, lowered blood pressure, and decreased blood insulin and IGF1 levels as compared with the standard diet168. The intervention was safe with no grade 3 or 4 adverse events and a dropout rate (25%) that was better than calorie restriction intervention trials. When compared head to head with calorie restriction in a randomized controlled trial of 60 obese women, 2 months of FMD led to similar weight loss and improvements in markers of insulin resistance and muscle mass, albeit these were not measured using gold-standard methods169. Other forms of intermittent fasting, such as time-restricted feeding, are under investigation (Box 2).
In mouse models of cancer, cycles of fasting reduce tumorigenesis and slow tumour growth170,171,172,173. When paired with traditional anticancer therapy, FMD cycles can enhance therapeutic efficacy. For example, fasting cycles enhance gemcitabine efficacy in mice with prostate cancer xenografts174, and the FMD strategy leads to durable remission of breast tumours in mice when combined with anti-oestrogen therapy and cyclin-dependent kinase 4 (CDK4) and CDK6 (hereafter CDK4/6) inhibition, a clinically relevant combination13. The beneficial effects of FMD are dependent on low levels of insulin, leptin and IGF1; when these hormones are co-administered to mice receiving FMD, the diet’s antitumour effects are abolished13.
FMD is a promising clinical intervention that is rapidly advancing along the clinical development pipeline (Fig. 3). In most cases, FMD is safe and feasible with rates of grade 3 or 4 adverse events of 13% and dropout rates of 24% after 3 FMD cycles in subjects with cancer13,16,175. The beneficial metabolic effects on insulin, IGF1 and leptin observed in mice appear to be conserved in subjects with cancer while preserving body weight13,15,16,171,175. These changes lower immunosuppressive peripheral cells and enhance the intratumour cytotoxic response16. Moreover, FMD is safe in combination with a CDK4/6 inhibitor and may improve efficacy13. We eagerly await more clinical studies with formal tumour outcomes176.
Very low carbohydrate (ketogenic) diets
Some of the systemic metabolic benefits of calorie restriction and fasting can be recapitulated by diets with altered macronutrient ratios. For example, very low carbohydrate diets (VLCDs) or low-fat diets (LFDs) suppress food intake and alter tumorigenic hormones, as compared with standard diets177,178. These diets have been studied in patients with cancer for decades, showing adequate safety, feasibility and, in some cases, anticancer efficacy data.
The VLCD was clinically described in the 1920s as a means of sustaining the epilepsy-alleviating effects of fasting179,180. In this ‘classic’ form, the VLCD has very low carbohydrate intake of ≤15 g per day (<5% of calories), a moderate to low protein intake and enough fat to make up the rest of the calorie expenditure181. Typically, the fats arise from coconut oil, butter, eggs, avocados, cheese and meat. This style of eating has been shown to promote and maintain very low levels of serum insulin in children with epilepsy, adults with obesity with metabolic syndrome and patients with cancer182,183,184,185,186. Because of the lack of carbohydrates and glycaemic load, VLCDs are more effective in improving metabolic parameters associated with glycaemic, weight and lipid controls in patients with high body mass index, especially those with pre-existing diabetes, as compared with LFDs187.
The long-term effects of eating a VLCD have not been evaluated in large, prospective, randomized controlled clinical trials; however, there is supportive evidence of safety. In a non-randomized study of participants with type 2 diabetes over 2 years, an intervention including telemedicine, health coaching and a personalized VLCD improved metabolic markers with no reported adverse events and a 26% dropout rate188. In patients without obesity or metabolic disease, the diet may cause low-grade fatigue, headache, nausea, constipation, hypoglycaemia and acidosis within the first few days to weeks189,190. Low-grade dehydration, hepatitis, pancreatitis, hypertriglyceridemia, hyperuricaemia, hypercholesterolaemia, hypomagnesaemia and hyponatraemia have been reported in older people191.
Despite the potential for adverse events, a systematic review of 13 studies using a VLCD in subjects with various cancers concluded that this approach is safe, especially when compared with traditional anticancer therapy192. For example, Cohen et al. performed a 12-week randomized controlled trial in women with ovarian or uterine cancer to test the effects of a VLCD intervention on metabolic parameters183. Adherence to the diet was excellent (dropout rate 19%), and there were only low-grade adverse events including hunger, constipation, fatigue, muscle cramps, diarrhoea and cold extremities. Subjects displayed selective loss of fat mass, retention of lean mass and no change in blood lipids182,183,193. Importantly, those on the VLCD had significantly lower measures of insulin production and higher physical function scores193. No effects on tumour outcomes have been reported from this cohort. In other situations, the VLCD is not well tolerated. For example, only 4 of 12 subjects with locally advanced head and neck cancer could complete a 5-week VLCD intervention, and several adverse events were noted including grade 2 nausea, grade 3 fatigue, grade 4 hyperuricaemia and grade 3 acute pancreatitis194. The VLCD is also poorly tolerated in subjects with lung and pancreatic cancer. For example, only 3 of 9 subjects with these cancers could comply with the diet over 2 years195. Patients with head and neck, lung and pancreas cancers have a high risk of developing cachexia196, which may be limiting the ability to comply with a VLCD.
There is growing enthusiasm for the use of the VLCD as an anticancer intervention. A dietary pattern lower in carbohydrates and protein, and higher in fat is associated with longer survival time in patients with pancreatic cancer115. However, it remains unclear whether these patients will be able to tolerate this dietary pattern given the high predilection for weight loss197. This question is currently under investigation198. There are also promising data for use of the VLCD in women with breast cancer. In a randomized controlled trial in 80 subjects with breast cancer undergoing chemotherapy, a 12-week VLCD intervention reduced the tumour diameter as compared with the controls on a standard diet199. We interpret these results with caution as the Response Evaluation Criteria in Solid Tumours (RECIST)200 were not used to measure tumour size and dietary fat intake is associated with increased risk for breast cancer development and recurrence in certain subgroups201,202,203,204,205. Nevertheless, these are exciting preliminary data that support the need for future studies to better define the specific patient subsets that will most benefit from the VLCD.
LFDs restrict fat intake to less than 30% of total calories per day and emphasize intake of vegetables, fruits and whole grains. LFDs safely promote weight loss, fat loss, lower blood cholesterol and reduced food intake in subjects without cancer206. In fact, several LFDs are endorsed by major medical associations including the Dietary Approaches to Stop Hypertension (DASH) diet, the US Department of Agriculture food pattern, a vegan diet and the American Heart Association (AHA) diet207,208,209,210.
Unlike the other dietary interventions discussed in this Review, LFDs have been rigorously tested in large populations of subjects with cancer. The Women’s Health Initiative Dietary Modification (WHI DM) trial was a prospective, randomized controlled study in postmenopausal women designed to examine the long-term benefits and risks of a LFD on breast cancer, CRC and cardiovascular disease203,211. Although no long-term reduction in cancer risk or overall mortality was observed212, the LFD intervention lowered the incidence of deaths after breast cancer diagnosis203. This finding was more directly assessed in two randomized trials: the Women’s Intervention Nutrition Study (WINS) and the Women’s Healthy Eating and Living (WHEL) study. Both were randomized trials to test the effects of a LFD intervention in women with previously treated, early-stage breast cancer204,205. Both trials achieved about a 9% reduction in dietary fat intake between intervention and control groups with about a 30% dropout rate after 3 years213. Although there were some notable differences in the populations studied and outcomes reported213, the WINS and WHEL data suggest that LFDs have beneficial effects only in subgroups of patients with breast cancer. For example, there was a diet-induced reduction in distal recurrences among women who did not experience hot flashes214. This benefit may be due to the diet’s ability to reduce oestradiol concentrations215,216, which may be irrelevant in the age of ER blockade. This question is currently under investigation217.
In regard to prostate cancer, the benefits of a LFD are less clear. Diets high in fat and saturated fat induce a MYC gene expression signature that independently predicts prostate cancer progression and death218. This finding has led researchers to study the LFD in several cohorts of men with prostate cancer. Despite good adherence, the diet does not change serum prostate-specific antigen, sex hormones, insulin or IGF1 in this setting219,220,221. Tumours may evade the effects of a LFD by upregulating fatty acid synthesis so clinical efficacy might be improved by combining a LFD with inhibitors of this pathway222.
Other dietary interventions
There are numerous other means to modify the diet that might impede tumour growth. For example, depletion of specific amino acids such as serine and glycine, cysteine and methionine show promising anticancer efficacy in preclinical models (nicely reviewed elsewhere11), but there are no clinical data yet. Restricting these amino acids in preclinical models depletes tumours of necessary precursors for one-carbon metabolism, and thereby inhibits established tumour growth223. Furthermore, the addition of certain sugars, vitamins and amino acids to the diet may alter nutrient flux and enhance anticancer therapy (recently reviewed in detail10). Early-phase clinical studies are ongoing for many of these approaches.
Towards precision nutrition for cancer
Precision medicine promises to deliver the right drug to the right patient at the right time. This approach is helping transform the treatment of cancer from one-size-fits-all to bespoke interventions for clearly denoted cancer subtypes. A similar course could be taken for delivering dietary interventions to support cancer therapy. We propose targeting dietary interventions to vulnerable tumour tissue types with distinct histological and molecular features (Table 1). For example, ER+ breast cancers frequently develop PIK3CA mutations to evade hormonal therapy, as discussed above. These patients may benefit from combining hormonal and PI3K inhibitor therapy with a VLCD, which lowers insulin and reduces the tumour’s ability to maintain rapid nutrient uptake12,13. By contrast, because triple-negative breast cancers may rely more heavily on exogenous fatty acids, a LFD may be a better intervention80. CRC growth can be promoted by fructose and dietary fats, and thus a plant-based LFD with no added sugar, which has been shown to be feasible in humans224, may be appropriate for these patients. Pancreatic cancer cells, meanwhile, rely on exogenous unsaturated fatty acids, and thus a calorie-restricted or VLCD specifically high in saturated fats may be effective115.
Diet interventions should be paired with synergistic pharmacological therapies because it is unlikely that diet alone will be strong enough to combat tumour progression. For example, data in mice indicate that FMDs and VLCDs can lead to durable tumour regression when they are paired with CDK4/6 and PI3K inhibitors, respectively12,13. Mouse studies and human genomic analyses also endorse the combination of amino acid-depleted diets and diets low in unsaturated fats with inhibitors of metabolic enzymes such as phosphoglycerate dehydrogenase (PHGDH) and SCD, respectively115,223. The ability of calorie restriction and FMD to synergize with standard-of-care chemotherapy is under active investigation.
The field of precision nutrition is moving at a rapid pace with numerous pre-registered trials on the horizon. We would like to highlight several aspects to consider when planning a dietary intervention study in patients with cancer (Box 3). Of note, the field needs to better identify and catalogue diet-related adverse events. All effective anticancer interventions cause toxicity and the field needs to agree on the amount of toxicity that is acceptable from a dietary intervention. In a recently published study16, Vernieri et al. pre-specified a 20% threshold for severe (grade 3 or 4) adverse events arising from a FMD. Given that fasting may help mitigate the adverse effects of chemotherapy, this seems a reasonable cut-off value225. Even with adequate safety, a portion of subjects do not adhere to prescribed diets, even with adequate counselling and full menus provided. There are numerous reasons for this. There are neurohormonal pathways that strongly regulate behaviour in the setting of weight loss, and food carries sentimental value in our cultures, serving as a means to connect with loved ones on special occasions. Investigators should assume dropout rates of 20–30% during power calculations if the appropriate pilot data are not available in subjects with cancer. Additional studies are needed to find the optimal time to commence dietary interventions because some may only be effective in patients with early-stage cancers; we have limited information in this regard. Lastly, we know very little about the effects of dietary interventions on tumour metabolism, signalling and immunity in humans, and this should be investigated using appropriate pharmacodynamic read-outs.
Tumour tissue of origin and genetic driver mutations contribute to distinct metabolic preferences, which can be targeted with diet during cancer therapy. There is an overall impression by the lay press that ‘healthy eating’ will aid in the fight against cancer. Although this sentiment is supported by epidemiological data in the setting of cancer prevention6, it is important to remember that fighting cancer is a high-risk, high-reward endeavour and the acceptable limits of toxicity need to be balanced with the potential for a successful outcome. Dietary intervention studies have relatively high dropout rates and may impose additional toxicity; however, the promising preclinical and early clinical data support their further development. We suggest maximizing the likelihood of success by designing studies that test diet–drug combination therapies based on the tumour tissue of origin, genetic alterations and the degree of interaction with systemic hormones and metabolites. Future studies should include appropriate pharmacodynamic read-outs that catalogue the effects of each diet on tumour growth, metabolism and microenvironment composition, which are all understudied in this field.
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This work was supported, in part, by National Institutes of Health (NIH) K08CA230318 (M.D.G.), 2020 AACR–The Mark Foundation for Cancer Research ‘Science of the Patient’ (SOP) Grant Number 20-60-51-GONC (M.D.G.), NIH R35CA197588 (L.C.C.) and a grant from the Breast Cancer Research Foundation (L.C.C.).
L.C.C. is a founder, shareholder and member of the scientific advisory board of Agios Pharmaceuticals and a founder and former member of the scientific advisory board of Ravenna Pharmaceuticals (previously Petra Pharmaceuticals). These companies are developing novel therapies for cancer. L.C.C. has received research funding from Ravenna Pharmaceuticals outside the covered work. L.C.C. and M.D.G. are co-founders and shareholders of Faeth Therapeutics, which are developing dietary and pharmacologic therapies for cancer. M.D.G. has received speaking and/or consulting fees from Pfizer Inc., Novartis AG, Petra Pharmaceuticals, Scorpion Therapeutics and Faeth Therapeutics. M.D.G.’s laboratory has received financial support from Pfizer Inc. outside the covered work. All other authors report no competing interests.
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- Electromotive force
The electric potential generated by the position of charged molecules, such as when partitioned across a membrane.
- ATP synthase
A mitochondrial enzyme that phosphorylates ADP to make ATP.
- Ketone bodies
Metabolites such as β-hydroxybutyrate and acetoacetate, which are produced during hepatic fatty acid oxidation and can be used as energy substrates by some tissues.
- Triple-negative breast tumours
Breast tumours with low levels of oestrogen receptor (ER), progesterone receptor and HER2 overexpression and/or amplification. Typically, these tumours carry a worse prognosis than other types.
- Proliferative phase of the endometrial cycle
The phase of the endometrial cycle in which the endometrial cells rapidly proliferate in preparation for possible implantation of a fertilized embryo.
Typically referring to the ‘refilling’ or ‘fuelling’ of the tricarboxylic acid (TCA) cycle with amino acids to drive biosynthetic reactions.
A metabolic state defined by low levels of insulin, high hepatic fatty acid oxidation and increased levels of circulating ketone bodies.
- Metabolic dysfunction
A general term collating multiple abnormalities in glucose and lipid homeostasis such as dyslipidaemia, obesity, insulin resistance, glucose intolerance, diabetes and fatty liver disease.
- Response Evaluation Criteria in Solid Tumours
(RECIST). A validated and consistent radiologic methodology to evaluate the activity and efficacy of new cancer therapeutics in solid tumours.
- One-carbon metabolism
Referring to both the folate and methionine cycles that allow cells to generate one-carbon units for the biosynthesis of important anabolic precursors and for methylation reactions.
- Eastern Cooperative Oncology Group
(ECOG). A standardized clinical scoring algorithm that describes a patient’s level of functioning in terms of their ability to care for themself, daily activity and physical ability (walking, working and so on).
- Subjective Global Assessment
(SGA). A clinical scoring algorithm using information from a patient interview and physical examination that healthcare providers use to determine a person’s nutritional status.
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Taylor, S.R., Falcone, J.N., Cantley, L.C. et al. Developing dietary interventions as therapy for cancer. Nat Rev Cancer 22, 452–466 (2022). https://doi.org/10.1038/s41568-022-00485-y