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Dietary modifications for enhanced cancer therapy


Tumours depend on nutrients supplied by the host for their growth and survival. Modifications to the host’s diet can change nutrient availability in the tumour microenvironment, which might represent a promising strategy for inhibiting tumour growth. Dietary modifications can limit tumour-specific nutritional requirements, alter certain nutrients that target the metabolic vulnerabilities of the tumour, or enhance the cytotoxicity of anti-cancer drugs. Recent reports have suggested that modification of several nutrients in the diet can alter the efficacy of cancer therapies, and some of the newest developments in this quickly expanding field are reviewed here. The results discussed indicate that the dietary habits and nutritional state of a patient must be taken into account during cancer research and therapy.

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Fig. 1: Mechanisms of tumour inhibition by dietary modifications.
Fig. 2: Glucose metabolism in cancer cells.
Fig. 3: Serine metabolism in cancer cells.


  1. 1.

    Sullivan, M. R. et al. Quantification of microenvironmental metabolites in murine cancers reveals determinants of tumor nutrient availability. eLife 8, e44235 (2019).

    PubMed  PubMed Central  Google Scholar 

  2. 2.

    Cantor, J. R. et al. Physiologic medium rewires cellular metabolism and reveals uric acid as an endogenous inhibitor of UMP synthase. Cell 169, 258–272.e217 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. 3.

    Muir, A. et al. Environmental cystine drives glutamine anaplerosis and sensitizes cancer cells to glutaminase inhibition. eLife 6, e27713 (2017).

    PubMed  PubMed Central  Google Scholar 

  4. 4.

    Davidson, S. M. et al. Environment impacts the metabolic dependencies of Ras-driven non-small cell lung cancer. Cell Metab. 23, 517–528 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. 5.

    Torrence, M. E. & Manning, B. D. Nutrient sensing in cancer. Annu. Rev. Cancer Biol. 2, 251–269 (2018). This review addresses a topic (not discussed here) that is key for understanding the consequences of dietary modifications that change nutrient availability at the tumour microenvironment, such as the dietary modifications listed above.

    Google Scholar 

  6. 6.

    Hotamisligil, G. S. Inflammation, metaflammation and immunometabolic disorders. Nature 542, 177–185 (2017).

    ADS  CAS  PubMed  Google Scholar 

  7. 7.

    Zitvogel, L., Pietrocola, F. & Kroemer, G. Nutrition, inflammation and cancer. Nat. Immunol. 18, 843–850 (2017).

    CAS  PubMed  Google Scholar 

  8. 8.

    Soldati, L. et al. The influence of diet on anti-cancer immune responsiveness. J. Transl. Med. 16, 75 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. 9.

    Nencioni, A., Caffa, I., Cortellino, S. & Longo, V. D. Fasting and cancer: molecular mechanisms and clinical application. Nat. Rev. Cancer 18, 707–719 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. 10.

    Di Francesco, A., Di Germanio, C., Bernier, M. & de Cabo, R. A time to fast. Science 362, 770–775 (2018).

    ADS  PubMed  Google Scholar 

  11. 11.

    Descamps, O., Riondel, J., Ducros, V. & Roussel, A. M. Mitochondrial production of reactive oxygen species and incidence of age-associated lymphoma in OF1 mice: effect of alternate-day fasting. Mech. Ageing Dev. 126, 1185–1191 (2005).

    CAS  PubMed  Google Scholar 

  12. 12.

    Berrigan, D., Perkins, S. N., Haines, D. C. & Hursting, S. D. Adult-onset calorie restriction and fasting delay spontaneous tumorigenesis in p53-deficient mice. Carcinogenesis 23, 817–822 (2002).

    CAS  PubMed  Google Scholar 

  13. 13.

    Lee, C. et al. Fasting cycles retard growth of tumors and sensitize a range of cancer cell types to chemotherapy. Sci. Transl. Med. 4, 124ra27 (2012).

    PubMed  PubMed Central  Google Scholar 

  14. 14.

    Lee, C. et al. Reduced levels of IGF-I mediate differential protection of normal and cancer cells in response to fasting and improve chemotherapeutic index. Cancer Res. 70, 1564–1572 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. 15.

    Brandhorst, S. et al. A periodic diet that mimics fasting promotes multi-system regeneration, enhanced cognitive performance, and healthspan. Cell Metab. 22, 86–99 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. 16.

    Locasale, J. W. The consequences of enhanced cell-autonomous glucose metabolism. Trends Endocrinol. Metab. 23, 545–551 (2012). This paper describes in depth the metabolic alterations that occur in cells that process abnormally high amount of glucose, such as transformed cells.

    CAS  PubMed  Google Scholar 

  17. 17.

    Belhocine, T. et al. 18FDG PET in oncology: the best and the worst (Review). Int. J. Oncol. 28, 1249–1261 (2006).

    PubMed  Google Scholar 

  18. 18.

    Gallagher, E. J. & LeRoith, D. Minireview: IGF, insulin, and cancer. Endocrinology 152, 2546–2551 (2011).

    CAS  PubMed  Google Scholar 

  19. 19.

    Warburg, O. On the origin of cancer cells. Science 123, 309–314 (1956).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Courtney, K. D. et al. Isotope tracing of human clear cell renal cell carcinomas demonstrates suppressed glucose oxidation in vivo. Cell Metab. 28, 793–800.e2 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Vander Heiden, M. G., Cantley, L. C. & Thompson, C. B. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 324, 1029–1033 (2009).

    ADS  Google Scholar 

  22. 22.

    Fruman, D. A. et al. The PI3K pathway in human disease. Cell 170, 605–635 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. 23.

    Saxton, R. A. & Sabatini, D. M. mTOR signaling in growth, metabolism, and disease. Cell 169, 361–371 (2017).

    CAS  PubMed  Google Scholar 

  24. 24.

    Fontana, L., Meyer, T. E., Klein, S. & Holloszy, J. O. Long-term calorie restriction is highly effective in reducing the risk for atherosclerosis in humans. Proc. Natl Acad. Sci. USA 101, 6659–6663 (2004).

    ADS  CAS  PubMed  Google Scholar 

  25. 25.

    Brandhorst, S. & Longo, V. D. Fasting and caloric restriction in cancer prevention and treatment. Recent Results Cancer Res. 207, 241–266 (2016).

    CAS  PubMed  Google Scholar 

  26. 26.

    Weber, D. D., Aminazdeh-Gohari, S. & Kofler, B. Ketogenic diet in cancer therapy. Aging (Albany NY) 10, 164–165 (2018).

    Google Scholar 

  27. 27.

    Allen, B. G. et al. Ketogenic diets as an adjuvant cancer therapy: history and potential mechanism. Redox Biol. 2, 963–970 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. 28.

    Champ, C. E. et al. Targeting metabolism with a ketogenic diet during the treatment of glioblastoma multiforme. J. Neurooncol. 117, 125–131 (2014).

    CAS  PubMed  Google Scholar 

  29. 29.

    Seyfried, T. N., Sanderson, T. M., El-Abbadi, M. M., McGowan, R. & Mukherjee, P. Role of glucose and ketone bodies in the metabolic control of experimental brain cancer. Br. J. Cancer 89, 1375–1382 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. 30.

    Martuscello, R. T. et al. A supplemented high-fat low-carbohydrate diet for the treatment of glioblastoma. Clin. Cancer Res. 22, 2482–2495 (2016).

    CAS  PubMed  Google Scholar 

  31. 31.

    Curry, N. L. et al. Pten-null tumors cohabiting the same lung display differential AKT activation and sensitivity to dietary restriction. Cancer Discov. 3, 908–921 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. 32.

    Kalaany, N. Y. & Sabatini, D. M. Tumours with PI3K activation are resistant to dietary restriction. Nature 458, 725–731 (2009). This study emphasizes the key role played by glucose as an upstream activator of PI3K signalling in cancer cell proliferation, by showing in vivo that tumours with constitutive PI3K activation can survive glucose restriction.

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  33. 33.

    Hopkins, B. D. et al. Suppression of insulin feedback enhances the efficacy of PI3K inhibitors. Nature 560, 499–503 (2018). This paper demonstrates that a combination of dietary and pharmacological insulin inhibition results in reduced pro-oncogenic signalling through mTOR, enhanced tumour inhibition and improved survival of tumour-bearing mice in several cancer models.

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  34. 34.

    Carracedo, A., Cantley, L. C. & Pandolfi, P. P. Cancer metabolism: fatty acid oxidation in the limelight. Nat. Rev. Cancer 13, 227–232 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. 35.

    Erickson, N., Boscheri, A., Linke, B. & Huebner, J. Systematic review: isocaloric ketogenic dietary regimes for cancer patients. Med. Oncol. 34, 72 (2017). This systematic review summarizes reports that have used a ketogenic diet in patients with cancer.

    CAS  PubMed  Google Scholar 

  36. 36.

    Fine, E. J. et al. Targeting insulin inhibition as a metabolic therapy in advanced cancer: a pilot safety and feasibility dietary trial in 10 patients. Nutrition 28, 1028–1035 (2012).

    CAS  PubMed  Google Scholar 

  37. 37.

    Jansen, N. & Walach, H. The development of tumours under a ketogenic diet in association with the novel tumour marker TKTL1: a case series in general practice. Oncol. Lett. 11, 584–592 (2016).

    CAS  PubMed  Google Scholar 

  38. 38.

    Maino Vieytes, C. A., Taha, H. M., Burton-Obanla, A. A., Douglas, K. G. & Arthur, A. E. Carbohydrate nutrition and the risk of cancer. Curr. Nutr. Rep. 8, 230–239 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. 39.

    Hannou, A. A. et al. Fructose metabolism and metabolic disease. J. Clin. Invest. 128, 545–555 (2018).

    PubMed  PubMed Central  Google Scholar 

  40. 40.

    Makarem, N., Bandera, E. V., Nicholson, J. M. & Parekh, N. Consumption of sugars, sugary foods, and sugary beverages in relation to cancer risk: a systematic review of longitudinal studies. Annu. Rev. Nutr. 38, 17–39 (2018).

    CAS  PubMed  Google Scholar 

  41. 41.

    Jang, C. et al. The small intestine converts dietary fructose into glucose and organic acids. Cell Metab. 27, 351–361.e353 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. 42.

    Douard, V. & Ferraris, R. P. The role of fructose transporters in diseases linked to excessive fructose intake. J. Physiol. (Lond.) 591, 401–414 (2013).

    CAS  Google Scholar 

  43. 43.

    Jin, C., Gong, X. & Shang, Y. GLUT5 increases fructose utilization in ovarian cancer. OncoTargets Ther. 12, 5425–5436 (2019).

    CAS  Google Scholar 

  44. 44.

    Weng, Y., Zhu, J., Chen, Z., Fu, J. & Zhang, F. Fructose fuels lung adenocarcinoma through GLUT5. Cell Death Dis. 9, 557 (2018).

    PubMed  PubMed Central  Google Scholar 

  45. 45.

    Su, C., Li, H. & Gao, W. GLUT5 increases fructose utilization and promotes tumor progression in glioma. Biochem. Biophys. Res. Commun. 500, 462–469 (2018).

    CAS  PubMed  Google Scholar 

  46. 46.

    Softic, S., Cohen, D. E. & Kahn, C. R. Role of dietary fructose and hepatic de novo lipogenesis in fatty liver disease. Dig. Dis. Sci. 61, 1282–1293 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. 47.

    Mai, B. H. & Yan, L. J. The negative and detrimental effects of high fructose on the liver, with special reference to metabolic disorders. Diabetes Metab. Syndr. Obes. 12, 821–826 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. 48.

    Goncalves, M. D. et al. High-fructose corn syrup enhances intestinal tumor growth in mice. Science 363, 1345–1349 (2019).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  49. 49.

    Kamata, S. et al. Dietary deprivation of each essential amino acid induces differential systemic adaptive responses in mice. Mol. Nutr. Food Res. 58, 1309–1321 (2014). This study demonstrates that deprivation of essential amino acids results in a systemic adaptive response that circumvents the systemic drop of the deprived amino acid as measured in the plasma.

    CAS  PubMed  Google Scholar 

  50. 50.

    Adibi, S. A., Modesto, T. A., Morse, E. L. & Amin, P. M. Amino acid levels in plasma, liver, and skeletal muscle during protein deprivation. Am. J. Physiol. 225, 408–414 (1973).

    CAS  PubMed  Google Scholar 

  51. 51.

    Gao, X. et al. Dietary methionine influences therapy in mouse cancer models and alters human metabolism. Nature 572, 397–401 (2019). This study compared the metabolic consequences of methionine restriction between patients with cancer and tumour-bearing mice, and found them to be similar. In addition, methionine restriction was shown to influence anti-cancer therapy.

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  52. 52.

    Hoffman, R. M. & Erbe, R. W. High in vivo rates of methionine biosynthesis in transformed human and malignant rat cells auxotrophic for methionine. Proc. Natl Acad. Sci. USA 73, 1523–1527 (1976). The work described here provides experimental proof that methionine auxotrophy in transformed cells stems not from an inability of these cells to synthesize methionine, but rather from their high demand for methionine.

    ADS  CAS  PubMed  Google Scholar 

  53. 53.

    Mentch, S. J. et al. Histone methylation dynamics and gene regulation occur through the sensing of one-carbon metabolism. Cell Metab. 22, 861–873 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. 54.

    Gu, X. et al. SAMTOR is an S-adenosylmethionine sensor for the mTORC1 pathway. Science 358, 813–818 (2017).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  55. 55.

    Eriksson, S., Prigge, J. R., Talago, E. A., Arnér, E. S. & Schmidt, E. E. Dietary methionine can sustain cytosolic redox homeostasis in the mouse liver. Nat. Commun. 6, 6479 (2015).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  56. 56.

    Guo, H. et al. Therapeutic tumor-specific cell cycle block induced by methionine starvation in vivo. Cancer Res. 53, 5676–5679 (1993).

    CAS  PubMed  Google Scholar 

  57. 57.

    Poirson-Bichat, F. et al. Methionine deprivation and methionine analogs inhibit cell proliferation and growth of human xenografted gliomas. Life Sci. 60, 919–931 (1997).

    CAS  PubMed  Google Scholar 

  58. 58.

    Liu, H. et al. Methionine and cystine double deprivation stress suppresses glioma proliferation via inducing ROS/autophagy. Toxicol. Lett. 232, 349–355 (2015).

    CAS  PubMed  Google Scholar 

  59. 59.

    Poirson-Bichat, F., Gonfalone, G., Bras-Gonçalves, R. A., Dutrillaux, B. & Poupon, M. F. Growth of methionine-dependent human prostate cancer (PC-3) is inhibited by ethionine combined with methionine starvation. Br. J. Cancer 75, 1605–1612 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. 60.

    Sinha, R. et al. Dietary methionine restriction inhibits prostatic intraepithelial neoplasia in TRAMP mice. Prostate 74, 1663–1673 (2014).

    CAS  PubMed  Google Scholar 

  61. 61.

    Komninou, D., Leutzinger, Y., Reddy, B. S. & Richie, J. P. Jr Methionine restriction inhibits colon carcinogenesis. Nutr. Cancer 54, 202–208 (2006).

    CAS  PubMed  Google Scholar 

  62. 62.

    Strekalova, E., Malin, D., Good, D. M. & Cryns, V. L. Methionine deprivation induces a targetable vulnerability in triple-negative breast cancer cells by enhancing TRAIL receptor-2 expression. Clin. Cancer Res. 21, 2780–2791 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. 63.

    Jeon, H. et al. Methionine deprivation suppresses triple-negative breast cancer metastasis in vitro and in vivo. Oncotarget 7, 67223–67234 (2016).

    PubMed  PubMed Central  Google Scholar 

  64. 64.

    Hens, J. R. et al. Methionine-restricted diet inhibits growth of MCF10AT1-derived mammary tumors by increasing cell cycle inhibitors in athymic nude mice. BMC Cancer 16, 349 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. 65.

    Miousse, I. R. et al. Modulation of dietary methionine intake elicits potent, yet distinct, anticancer effects on primary versus metastatic tumors. Carcinogenesis 39, 1117–1126 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. 66.

    Yu, D. et al. Short-term methionine deprivation improves metabolic health via sexually dimorphic, mTORC1-independent mechanisms. FASEB J. 32, 3471–3482 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. 67.

    Longchamp, A. et al. Amino acid restriction triggers angiogenesis via GCN2/ATF4 regulation of VEGF and H2S production. Cell 173, 117–129.e114 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. 68.

    Carmeliet, P. VEGF as a key mediator of angiogenesis in cancer. Oncology 69 (Suppl. 3), 4–10 (2005).

    CAS  PubMed  Google Scholar 

  69. 69.

    Orentreich, N., Matias, J. R., DeFelice, A. & Zimmerman, J. A. Low methionine ingestion by rats extends life span. J. Nutr. 123, 269–274 (1993).

    CAS  PubMed  Google Scholar 

  70. 70.

    Miller, R. A. et al. Methionine-deficient diet extends mouse lifespan, slows immune and lens aging, alters glucose, T4, IGF-I and insulin levels, and increases hepatocyte MIF levels and stress resistance. Aging Cell 4, 119–125 (2005).

    CAS  PubMed  Google Scholar 

  71. 71.

    Ables, G. P., Perrone, C. E., Orentreich, D. & Orentreich, N. Methionine-restricted C57BL/6J mice are resistant to diet-induced obesity and insulin resistance but have low bone density. PLoS One 7, e51357 (2012).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  72. 72.

    Malloy, V. L. et al. Methionine restriction decreases visceral fat mass and preserves insulin action in aging male Fischer 344 rats independent of energy restriction. Aging Cell 5, 305–314 (2006).

    CAS  PubMed  Google Scholar 

  73. 73.

    Labuschagne, C. F., van den Broek, N. J., Mackay, G. M., Vousden, K. H. & Maddocks, O. D. Serine, but not glycine, supports one-carbon metabolism and proliferation of cancer cells. Cell Rep. 7, 1248–1258 (2014).

    CAS  PubMed  Google Scholar 

  74. 74.

    DeNicola, G. M. et al. NRF2 regulates serine biosynthesis in non-small cell lung cancer. Nat. Genet. 47, 1475–1481 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. 75.

    Possemato, R. et al. Functional genomics reveal that the serine synthesis pathway is essential in breast cancer. Nature 476, 346–350 (2011).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  76. 76.

    Gravel, S. P. et al. Serine deprivation enhances antineoplastic activity of biguanides. Cancer Res. 74, 7521–7533 (2014).

    CAS  PubMed  Google Scholar 

  77. 77.

    Maddocks, O. D. K. et al. Modulating the therapeutic response of tumours to dietary serine and glycine starvation. Nature 544, 372–376 (2017).

    ADS  CAS  PubMed  Google Scholar 

  78. 78.

    Sullivan, M. R. et al. Increased serine synthesis provides an advantage for tumors arising in tissues where serine levels are limiting. Cell Metab. 29, 1410–1421.e1414 (2019).

    CAS  PubMed  Google Scholar 

  79. 79.

    Pacold, M. E. et al. A PHGDH inhibitor reveals coordination of serine synthesis and one-carbon unit fate. Nat. Chem. Biol. 12, 452–458 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. 80.

    Maddocks, O. D. et al. Serine starvation induces stress and p53-dependent metabolic remodelling in cancer cells. Nature 493, 542–546 (2013). The study provides evidence that serine starvation in vivo is harmful for p53-deficient tumours, and discusses the role of serine in oxidative stress management. 

    ADS  CAS  PubMed  Google Scholar 

  81. 81.

    Kanarek, N. et al. Histidine catabolism is a major determinant of methotrexate sensitivity. Nature 559, 632–636 (2018). This paper describes a dietary supplement that enhances the efficacy of a common chemotherapy drug in vivo.

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  82. 82.

    Newman, E. M., Nierenberg, D. W. & Santi, D. V. Selective killing of transformed cells by methotrexate with histidine deprivation or with alpha-amino alcohols. Cancer Res. 43, 4703–4708 (1983).

    CAS  PubMed  Google Scholar 

  83. 83.

    Gonzalez, P. S. et al. Mannose impairs tumour growth and enhances chemotherapy. Nature 563, 719–723 (2018). This research describes a rare example of a nutrient that is toxic for cancer cells but otherwise harmless, and that has the potential to be supplemented in the diet as an anti-cancer treatment.

    ADS  CAS  PubMed  Google Scholar 

  84. 84.

    Hijiya, N. & van der Sluis, I. M. Asparaginase-associated toxicity in children with acute lymphoblastic leukemia. Leuk. Lymphoma 57, 748–757 (2016).

    CAS  PubMed  Google Scholar 

  85. 85.

    Krall, A. S., Xu, S., Graeber, T. G., Braas, D. & Christofk, H. R. Asparagine promotes cancer cell proliferation through use as an amino acid exchange factor. Nat. Commun. 7, 11457 (2016).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  86. 86.

    Knott, S. R. V. et al. Asparagine bioavailability governs metastasis in a model of breast cancer. Nature 554, 378–381 (2018).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  87. 87.

    Dillon, B. J. et al. Incidence and distribution of argininosuccinate synthetase deficiency in human cancers: a method for identifying cancers sensitive to arginine deprivation. Cancer 100, 826–833 (2004).

    CAS  PubMed  Google Scholar 

  88. 88.

    Lind, D. S. Arginine and cancer. J. Nutr. 134 (Suppl.), 2837S–2841S (2004).

    CAS  PubMed  Google Scholar 

  89. 89.

    Kremer, J. C. et al. Arginine deprivation inhibits the Warburg effect and upregulates glutamine anaplerosis and serine biosynthesis in ASS1-deficient cancers. Cell Rep. 18, 991–1004 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. 90.

    Ensor, C. M., Holtsberg, F. W., Bomalaski, J. S. & Clark, M. A. Pegylated arginine deiminase (ADI-SS PEG20,000 mw) inhibits human melanomas and hepatocellular carcinomas in vitro and in vivo. Cancer Res. 62, 5443–5450 (2002).

    CAS  PubMed  Google Scholar 

  91. 91.

    Izzo, F. et al. Pegylated arginine deiminase treatment of patients with unresectable hepatocellular carcinoma: results from phase I/II studies. J. Clin. Oncol. 22, 1815–1822 (2004).

    CAS  PubMed  Google Scholar 

  92. 92.

    Poillet-Perez, L. et al. Autophagy maintains tumour growth through circulating arginine. Nature 563, 569–573 (2018).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  93. 93.

    Palmer, R. M., Ashton, D. S. & Moncada, S. Vascular endothelial cells synthesize nitric oxide from l-arginine. Nature 333, 664–666 (1988).

    ADS  CAS  PubMed  Google Scholar 

  94. 94.

    Ohshima, H. & Bartsch, H. Chronic infections and inflammatory processes as cancer risk factors: possible role of nitric oxide in carcinogenesis. Mutat. Res. 305, 253–264 (1994).

    CAS  PubMed  Google Scholar 

  95. 95.

    Poursaitidis, I. et al. Oncogene-selective sensitivity to synchronous cell death following modulation of the amino acid nutrient cystine. Cell Rep. 18, 2547–2556 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. 96.

    Cramer, S. L. et al. Systemic depletion of l-cyst(e)ine with cyst(e)inase increases reactive oxygen species and suppresses tumor growth. Nat. Med. 23, 120–127 (2017).

    CAS  PubMed  Google Scholar 

  97. 97.

    Farber, S. et al. The action of pteroylglutamic conjugates on man. Science 106, 619–621 (1947).

    ADS  CAS  PubMed  Google Scholar 

  98. 98.

    Farber, S. & Diamond, L. K. Temporary remissions in acute leukemia in children produced by folic acid antagonist, 4-aminopteroyl-glutamic acid. N. Engl. J. Med. 238, 787–793 (1948).

    CAS  PubMed  Google Scholar 

  99. 99.

    Wilson, P. M., Danenberg, P. V., Johnston, P. G., Lenz, H. J. & Ladner, R. D. Standing the test of time: targeting thymidylate biosynthesis in cancer therapy. Nat. Rev. Clin. Oncol. 11, 282–298 (2014).

    CAS  PubMed  Google Scholar 

  100. 100.

    Newman, A. C. & Maddocks, O. D. K. One-carbon metabolism in cancer. Br. J. Cancer 116, 1499–1504 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. 101.

    Pui, C. H. & Evans, W. E. Treatment of acute lymphoblastic leukemia. N. Engl. J. Med. 354, 166–178 (2006).

    CAS  PubMed  Google Scholar 

  102. 102.

    Suvalov, O. et al. One-carbon metabolism and nucleotide biosynthesis as attractive targets for anticancer therapy. Oncotarget 8, 23955–23977 (2017).

    Google Scholar 

  103. 103.

    Field, M. S., Lan, X., Stover, D. M. & Stover, P. J. Dietary uridine decreases tumorigenesis in the Apc Min/+ model of intestinal cancer. Curr. Dev. Nutr. 2, nzy013 (2018).

    PubMed  PubMed Central  Google Scholar 

  104. 104.

    DeBerardinis, R. J. et al. Beyond aerobic glycolysis: transformed cells can engage in glutamine metabolism that exceeds the requirement for protein and nucleotide synthesis. Proc. Natl Acad. Sci. USA 104, 19345–19350 (2007).

    ADS  CAS  PubMed  Google Scholar 

  105. 105.

    Cluntun, A. A., Lukey, M. J., Cerione, R. A. & Locasale, J. W. Glutamine metabolism in cancer: understanding the heterogeneity. Trends Cancer 3, 169–180 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  106. 106.

    Metallo, C. M. et al. Reductive glutamine metabolism by IDH1 mediates lipogenesis under hypoxia. Nature 481, 380–384 (2011).

    ADS  PubMed  PubMed Central  Google Scholar 

  107. 107.

    Biancur, D. E. et al. Compensatory metabolic networks in pancreatic cancers upon perturbation of glutamine metabolism. Nat. Commun. 8, 15965 (2017).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  108. 108.

    Lacey, J. M. & Wilmore, D. W. Is glutamine a conditionally essential amino acid? Nutr. Rev. 48, 297–309 (1990).

    CAS  PubMed  Google Scholar 

  109. 109.

    Moloney, J. N. & Cotter, T. G. ROS signalling in the biology of cancer. Semin. Cell Dev. Biol. 80, 50–64 (2018).

    CAS  PubMed  Google Scholar 

  110. 110.

    Son, J. et al. Glutamine supports pancreatic cancer growth through a KRAS-regulated metabolic pathway. Nature 496, 101–105 (2013).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  111. 111.

    Chakrabarti, G. et al. Targeting glutamine metabolism sensitizes pancreatic cancer to PARP-driven metabolic catastrophe induced by ß-lapachone. Cancer Metab. 3, 12 (2015).

    PubMed  PubMed Central  Google Scholar 

  112. 112.

    Momcilovic, M. et al. The GSK3 signaling axis regulates adaptive glutamine metabolism in lung squamous cell carcinoma. Cancer Cell 33, 905–921.e905 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. 113.

    Tajan, M. et al. A role for p53 in the adaptation to glutamine starvation through the expression of SLC1A3. Cell Metab. 28, 721–736.e6 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. 114.

    Tardito, S. et al. Glutamine synthetase activity fuels nucleotide biosynthesis and supports growth of glutamine-restricted glioblastoma. Nat. Cell Biol. 17, 1556–1568 (2015). This paper emphasizes the importance of assessment of nutrients manipulated by dietary modifications at the tumour microenvironment and not elsewhere, such as the plasma.

    CAS  PubMed  PubMed Central  Google Scholar 

  115. 115.

    Niklison-Chirou, M. V. et al. TAp73 is a marker of glutamine addiction in medulloblastoma. Genes Dev. 31, 1738–1753 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. 116.

    Yang, L. et al. Targeting stromal glutamine synthetase in tumors disrupts tumor microenvironment-regulated cancer cell growth. Cell Metab. 24, 685–700 (2016).

    CAS  PubMed  Google Scholar 

  117. 117.

    Coloff, J. L. et al. Differential glutamate metabolism in proliferating and quiescent mammary epithelial cells. Cell Metab. 23, 867–880 (2016).

    CAS  PubMed  Google Scholar 

  118. 118.

    Sayin, V. I. et al. Activation of the NRF2 antioxidant program generates an imbalance in central carbon metabolism in cancer. eLife 6, e28083 (2017).

    PubMed  PubMed Central  Google Scholar 

  119. 119.

    Sullivan, L. B. et al. Aspartate is an endogenous metabolic limitation for tumour growth. Nat. Cell Biol. 20, 782–788 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. 120.

    Garcia-Bermudez, J. et al. Aspartate is a limiting metabolite for cancer cell proliferation under hypoxia and in tumours. Nat. Cell Biol. 20, 775–781 (2018). This study studied the dependency of tumours on aspartate under hypoxic conditions, and it provides an interesting example of potential specificity of tumour targeting by dietary deprivation of nutrients that might be achieved by tumour-specific vulnerability, in this case owing to the hypoxic conditions at the tumour site.

    CAS  PubMed  PubMed Central  Google Scholar 

  121. 121.

    Birsoy, K. et al. An essential role of the mitochondrial electron transport chain in cell proliferation is to enable aspartate synthesis. Cell 162, 540–551 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  122. 122.

    Sousa, C. M. et al. Pancreatic stellate cells support tumour metabolism through autophagic alanine secretion. Nature 536, 479–483 (2016). This study shows that although alanine has a unique metabolic role in pancreatic ductal adenocarcinoma, it is not likely to be a good target for dietary modifications because it is supplied to the tumour by surrounding stroma cells, illustrating the importance of understanding a tumour’s sources of nutrition.

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  123. 123.

    Carracedo, A. et al. A metabolic prosurvival role for PML in breast cancer. J. Clin. Invest. 122, 3088–3100 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  124. 124.

    Schafer, Z. T. et al. Antioxidant and oncogene rescue of metabolic defects caused by loss of matrix attachment. Nature 461, 109–113 (2009).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  125. 125.

    Camarda, R. et al. Inhibition of fatty acid oxidation as a therapy for MYC-overexpressing triple-negative breast cancer. Nat. Med. 22, 427–432 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  126. 126.

    Zaugg, K. et al. Carnitine palmitoyltransferase 1C promotes cell survival and tumor growth under conditions of metabolic stress. Genes Dev. 25, 1041–1051 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  127. 127.

    Caro, P. et al. Metabolic signatures uncover distinct targets in molecular subsets of diffuse large B cell lymphoma. Cancer Cell 22, 547–560 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  128. 128.

    Tucci, J. et al. Switch to low-fat diet improves outcome of acute lymphoblastic leukemia in obese mice. Cancer Metab. 6, 15 (2018).

    PubMed  PubMed Central  Google Scholar 

  129. 129.

    Beyaz, S. et al. High-fat diet enhances stemness and tumorigenicity of intestinal progenitors. Nature 531, 53–58 (2016).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  130. 130.

    Pike, L. S., Smift, A. L., Croteau, N. J., Ferrick, D. A. & Wu, M. Inhibition of fatty acid oxidation by etomoxir impairs NADPH production and increases reactive oxygen species resulting in ATP depletion and cell death in human glioblastoma cells. Biochim. Biophys. Acta 1807, 726–734 (2011).

    CAS  PubMed  Google Scholar 

  131. 131.

    Jeon, S. M., Chandel, N. S. & Hay, N. AMPK regulates NADPH homeostasis to promote tumour cell survival during energy stress. Nature 485, 661–665 (2012).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  132. 132.

    Yang, C. et al. Glioblastoma cells require glutamate dehydrogenase to survive impairments of glucose metabolism or Akt signaling. Cancer Res. 69, 7986–7993 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  133. 133.

    Hensley, C. T., Wasti, A. T. & DeBerardinis, R. J. Glutamine and cancer: cell biology, physiology, and clinical opportunities. J. Clin. Invest. 123, 3678–3684 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  134. 134.

    Hosios, A. M. et al. Amino acids rather than glucose account for the majority of cell mass in proliferating mammalian cells. Dev. Cell 36, 540–549 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  135. 135.

    Psychogios, N. et al. The human serum metabolome. PLoS ONE 6, e16957 (2011).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  136. 136.

    Di Biase, S. et al. Fasting-Mimicking Diet Reduces HO-1 to promote T cell-mediated tumor cytotoxicity. Cancer Cell 30, 136–146 (2016).

    PubMed  PubMed Central  Google Scholar 

  137. 137.

    Pietrocola, F. et al. Caloric restriction mimetics enhance anticancer immunosurveillance. Cancer Cell 30, 147–160 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  138. 138.

    Lussier, D. M. et al. Enhanced immunity in a mouse model of malignant glioma is mediated by a therapeutic ketogenic diet. BMC Cancer 16, 310 (2016).

    PubMed  PubMed Central  Google Scholar 

  139. 139.

    Geiger, R. et al. l-Arginine modulates T cell metabolism and enhances survival and anti-tumor activity. Cell 167, 829–842.e813 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  140. 140.

    Hui, S. et al. Glucose feeds the TCA cycle via circulating lactate. Nature 551, 115–118 (2017).

    ADS  PubMed  PubMed Central  Google Scholar 

  141. 141.

    Faubert, B. et al. Lactate metabolism in human lung tumors. Cell 171, 358–371.e359 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  142. 142.

    Gao, X. et al. Serine availability influences mitochondrial dynamics and function through lipid metabolism. Cell Rep. 22, 3507–3520 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  143. 143.

    Mattaini, K. R., Sullivan, M. R. & Vander Heiden, M. G. The importance of serine metabolism in cancer. J. Cell Biol. 214, 249–257 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  144. 144.

    Rajagopalan, K. N. & DeBerardinis, R. J. Role of glutamine in cancer: therapeutic and imaging implications. J. Nuclear Med. 52, 1005–1008 (2011).

    CAS  Google Scholar 

  145. 145.

    Zhang, J. et al. Asparagine plays a critical role in regulating cellular adaptation to glutamine depletion. Mol. Cell 56, 205–218 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  146. 146.

    Pavlova, N. N. et al. As extracellular glutamine levels decline, asparagine becomes an essential amino acid. Cell Metab. 27, 428–438.e425 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  147. 147.

    Chan, W. K. et al. The glutaminase activity of l-asparaginase is not required for anticancer activity against ASNS-negative cells. Blood 123, 3596–3606 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

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We thank all members of the Sabatini lab, and members of the Pathology Department at Boston Children’s Hospital for providing the research environment that inspired the writing of this review; K. Hixon, L. A. Shinefeld, L. D. Schweitzer, L. Pernas, L. Chantranupong and B. D. Hopkins for helpful comments on the manuscript; L. Nip for the graphic design; and D. A. Guertin for his mentorship. This work was supported by grants from the NIH to D.M.S. (R01 CA103866, R01 CA129105 and R37 AI047389), and from the Lustgarten Foundation. Fellowship support was provided by the European Molecular Biology Organization (EMBO) (Long-Term Fellowship ALTF 350-2012) and the American Association for Cancer Research (16-40-38-KANA) to N.K., with additional support from by the Women in Science/Revson Foundation Award (Weizmann Institute) and The Advancement of Women in Science Award (The Hebrew University). N.K. and B.P. are supported by Boston Children’s Hospital and the Children’s Hospital Pathology Foundation. D.M.S. is an investigator of the Howard Hughes Medical Institute and an American Cancer Society Research Professor.

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N.K. wrote the first draft. B.P. and N.K. wrote and edited the final manuscript. D.M.S. provided substantial edits and suggestions for each of the drafts. All authors edited and approved the final manuscript.

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Correspondence to Naama Kanarek.

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Kanarek, N., Petrova, B. & Sabatini, D.M. Dietary modifications for enhanced cancer therapy. Nature 579, 507–517 (2020).

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