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Metabolic interplays between the tumour and the host shape the tumour macroenvironment

Nature Reviews Cancer (2025)Cite this article

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Abstract

Metabolic reprogramming of cancer cells and the tumour microenvironment are pivotal characteristics of cancers, and studying these processes offer insights and avenues for cancer diagnostics and therapeutics. Recent advancements have underscored the impact of host systemic features, termed macroenvironment, on facilitating cancer progression. During tumorigenesis, these inherent features of the host, such as germline genetics, immune profile and the metabolic status, influence how the body responds to cancer. In parallel, as cancer grows, it induces systemic effects beyond the primary tumour site and affects the macroenvironment, for example, through inflammation, the metabolic end-stage syndrome of cachexia, and metabolic dysregulation. Therefore, understanding the intricate metabolic interplay between the tumour and the host is a growing frontier in advancing cancer diagnosis and therapy. In this Review, we explore the specific contribution of the metabolic fitness of the host to cancer initiation, progression and response to therapy. We then delineate the complex metabolic crosstalk between the tumour, the microenvironment and the host, which promotes disease progression to metastasis and cachexia. The metabolic relationships among the host, cancer pathogenesis and the consequent responsive systemic manifestations during cancer progression provide new perspectives for mechanistic cancer therapy and improved management of patients with cancer.

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Fig. 1: The dynamic metabolic crosstalk between the host and cancer affects patient outcomes.
Fig. 2: The host nutritional status affects the metabolic macroenvironment and tissue environment.
Fig. 3: Interactions within the tumour and the tissue microenvironment impact cancer metabolism.
Fig. 4: Metabolic rewiring of metastatic cells depends on the local environment at a distant organ.

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References

  1. Bergers, G. & Fendt, S. M. The metabolism of cancer cells during metastasis. Nat. Rev. Cancer 21, 162–180 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Berenblum, I. The cocarcinogenic action of croton resin. Cancer Res. 1, 44–48 (1941).

    CAS  Google Scholar 

  3. Kawai, T., Autieri, M. V. & Scalia, R. Adipose tissue inflammation and metabolic dysfunction in obesity. Am. J. Physiol. Cell Physiol. 320, C375–C391 (2021).

    Article  CAS  PubMed  Google Scholar 

  4. Kaaks, R. & Lukanova, A. Energy balance and cancer: the role of insulin and insulin-like growth factor-I. Proc. Nutr. Soc. 60, 91–106 (2001).

    Article  CAS  PubMed  Google Scholar 

  5. Morigny, P., Boucher, J., Arner, P. & Langin, D. Lipid and glucose metabolism in white adipocytes: pathways, dysfunction and therapeutics. Nat. Rev. Endocrinol. 17, 276–295 (2021).

    Article  CAS  PubMed  Google Scholar 

  6. Cox, A. J., West, N. P. & Cripps, A. W. Obesity, inflammation, and the gut microbiota. Lancet Diabetes Endocrinol. 3, 207–215 (2015).

    Article  CAS  PubMed  Google Scholar 

  7. Van Hul, M. & Cani, P. D. The gut microbiota in obesity and weight management: microbes as friends or foe? Nat. Rev. Endocrinol. 19, 258–271 (2023).

    Article  PubMed  Google Scholar 

  8. Quail, D. F. & Dannenberg, A. J. The obese adipose tissue microenvironment in cancer development and progression. Nat. Rev. Endocrinol. 15, 139–154 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  9. Maguire, O. A. et al. Creatine-mediated crosstalk between adipocytes and cancer cells regulates obesity-driven breast cancer. Cell Metab. 33, 499–512.e6 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Kershaw, E. E. & Flier, J. S. Adipose tissue as an endocrine organ. J. Clin. Endocrinol. Metab. 89, 2548–2556 (2004).

    Article  CAS  PubMed  Google Scholar 

  11. Galic, S., Oakhill, J. S. & Steinberg, G. R. Adipose tissue as an endocrine organ. Mol. Cell Endocrinol. 316, 129–139 (2010).

    Article  CAS  PubMed  Google Scholar 

  12. Wiseman, H. & Halliwell, B. Damage to DNA by reactive oxygen and nitrogen species: role in inflammatory disease and progression to cancer. Biochem. J. 313, 17–29 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Ohnishi, S. et al. DNA damage in inflammation-related carcinogenesis and cancer stem cells. Oxid. Med. Cell Longev. 2013, 387014 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  14. Hotamisligil, G. S., Shargill, N. S. & Spiegelman, B. M. Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science 259, 87–91 (1993).

    Article  CAS  PubMed  Google Scholar 

  15. Feinstein, R., Kanety, H., Papa, M. Z., Lunenfeld, B. & Karasik, A. Tumor necrosis factor-alpha suppresses insulin-induced tyrosine phosphorylation of insulin receptor and its substrates. J. Biol. Chem. 268, 26055–26058 (1993).

    Article  CAS  PubMed  Google Scholar 

  16. Cowey, S. & Hardy, R. W. The metabolic syndrome: a high-risk state for cancer? Am. J. Pathol. 169, 1505–1522 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Schwingshackl, L., Schwedhelm, C., Galbete, C. & Hoffmann, G. Adherence to Mediterranean diet and risk of cancer: an updated systematic review and meta-analysis. Nutrients https://doi.org/10.3390/nu9101063 (2017).

  18. Wang, T., Masedunskas, A., Willett, W. C. & Fontana, L. Vegetarian and vegan diets: benefits and drawbacks. Eur. Heart J. 44, 3423–3439 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Abe, C. et al. A longitudinal association between the Traditional Japanese Diet Score and incidence and mortality of breast cancer-an ecological study. Eur. J. Clin. Nutr. 75, 929–936 (2021).

    Article  PubMed  Google Scholar 

  20. Takasu, A. et al. Daily diet and nutrition risk factors for gastric cancer incidence in a Japanese population. Gut Liver 18, 602–610 (2024).

    Article  PubMed  PubMed Central  Google Scholar 

  21. Huang, J. et al. Association between plant and animal protein intake and overall and cause-specific mortality. JAMA Intern. Med. 180, 1173–1184 (2020).

    Article  CAS  PubMed  Google Scholar 

  22. Farvid, M. S. et al. Consumption of red meat and processed meat and cancer incidence: a systematic review and meta-analysis of prospective studies. Eur. J. Epidemiol. 36, 937–951 (2021).

    Article  PubMed  Google Scholar 

  23. Dyar, K. A. et al. Atlas of circadian metabolism reveals system-wide coordination and communication between clocks. Cell 174, 1571–1585.e11 (2018). This work describes comprehensive maps of circadian metabolism across mouse tissues in the context of systemic energy balance and under chronic nutrient stress (high fat diet), revealing a key role of circadian rhythm in tissue nutrient availability.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Sullivan, M. R. et al. Quantification of microenvironmental metabolites in murine cancers reveals determinants of tumor nutrient availability. eLife https://doi.org/10.7554/eLife.44235 (2019).

  25. Allen, A. M., Hicks, S. B., Mara, K. C., Larson, J. J. & Therneau, T. M. The risk of incident extrahepatic cancers is higher in non-alcoholic fatty liver disease than obesity — a longitudinal cohort study. J. Hepatol. 71, 1229–1236 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  26. Mahale, P. et al. Hepatitis C virus infection and the risk of cancer among elderly US adults: a registry-based case-control study. Cancer 123, 1202–1211 (2017).

    Article  PubMed  Google Scholar 

  27. Pol, S., Vallet-Pichard, A. & Hermine, O. Extrahepatic cancers and chronic HCV infection. Nat. Rev. Gastroenterol. Hepatol. 15, 283–290 (2018).

    Article  PubMed  Google Scholar 

  28. Sabbagh, C. et al. Management of colon cancer in patients with cirrhosis: a review. Surg. Oncol. 24, 187–193 (2015).

    Article  CAS  PubMed  Google Scholar 

  29. Yoshimoto, S. et al. Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome. Nature 499, 97–101 (2013).

    Article  CAS  PubMed  Google Scholar 

  30. Tilg, H. & Moschen, A. R. Mechanisms behind the link between obesity and gastrointestinal cancers. Best Pract. Res. Clin. Gastroenterol. 28, 599–610 (2014).

    Article  CAS  PubMed  Google Scholar 

  31. Goldman, O. et al. Early infiltration of innate immune cells to the liver depletes HNF4α and promotes extrahepatic carcinogenesis. Cancer Discov. https://doi.org/10.1158/2159-8290.CD-22-1062 (2023).

  32. Kut, E. & Menekse, S. Prognostic significance of pretreatment albumin-bilirubin (ALBI) grade and platelet-albumin-bilirubin (PALBI) grade in patients with small cell lung cancer. Sci. Rep. 14, 1371 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Drapela, S., Ilter, D. & Gomes, A. P. Metabolic reprogramming: a bridge between aging and tumorigenesis. Mol. Oncol. 16, 3295–3318 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Ross, J. M. et al. High brain lactate is a hallmark of aging and caused by a shift in the lactate dehydrogenase A/B ratio. Proc. Natl Acad. Sci. USA 107, 20087–20092 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Fang, E. F. et al. NAD+ in aging: molecular mechanisms and translational implications. Trends Mol. Med. 23, 899–916 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Connor, K. M. et al. Understanding metabolic changes in aging bone marrow. Exp. Hematol. Oncol. 7, 13 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  37. Ding, J. et al. A metabolome atlas of the aging mouse brain. Nat. Commun. 12, 6021 (2021). This work presents a comprehensive metabolome atlas of the ageing mouse brain, highlighting region-specific and age-specific metabolic changes, providing a valuable resource for future studies.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Tchkonia, T. et al. Fat tissue, aging, and cellular senescence. Aging Cell 9, 667–684 (2010).

    Article  CAS  PubMed  Google Scholar 

  39. Palmer, A. K. & Jensen, M. D. Metabolic changes in aging humans: current evidence and therapeutic strategies. J. Clin. Invest. https://doi.org/10.1172/JCI158451 (2022).

  40. Salzer, M. C. et al. Identity noise and adipogenic traits characterize dermal fibroblast aging. Cell 175, 1575–1590.e22 (2018).

    Article  CAS  PubMed  Google Scholar 

  41. Alicea, G. M. et al. Changes in aged fibroblast lipid metabolism induce age-dependent melanoma cell resistance to targeted therapy via the fatty acid transporter FATP2. Cancer Discov. 10, 1282–1295 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Baker, D. J. et al. Naturally occurring p16(Ink4a)-positive cells shorten healthy lifespan. Nature 530, 184–189 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Childs, B. G. et al. Senescent cells: an emerging target for diseases of ageing. Nat. Rev. Drug Discov. 16, 718–735 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Guo, J. et al. Aging and aging-related diseases: from molecular mechanisms to interventions and treatments. Signal Transduct. Target. Ther. 7, 391 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Nandy, A. et al. Altered osteoblast metabolism with aging results in lipid accumulation and oxidative stress mediated bone loss. Aging Dis. 15, 767–786 (2024).

    Article  PubMed  PubMed Central  Google Scholar 

  46. Zhang, W. et al. Nomogram predicts risk and prognostic factors for bone metastasis of pancreatic cancer: a population-based analysis. Front. Endocrinol. 12, 752176 (2021).

    Article  Google Scholar 

  47. Purushotham, A. et al. Age at diagnosis and distant metastasis in breast cancer — a surprising inverse relationship. Eur. J. Cancer 50, 1697–1705 (2014).

    Article  CAS  PubMed  Google Scholar 

  48. Hojman, P., Gehl, J., Christensen, J. F. & Pedersen, B. K. Molecular mechanisms linking exercise to cancer prevention and treatment. Cell Metab. 27, 10–21 (2018).

    Article  CAS  PubMed  Google Scholar 

  49. Laurens, C., de Glisezinski, I., Larrouy, D., Harant, I. & Moro, C. Influence of acute and chronic exercise on abdominal fat lipolysis: an update. Front. Physiol. 11, 575363 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  50. Nigro, P. et al. Exercise training remodels inguinal white adipose tissue through adaptations in innervation, vascularization, and the extracellular matrix. Cell Rep. 42, 112392 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Lin, T. C. & Hsiao, M. Leptin and cancer: updated functional roles in carcinogenesis, therapeutic niches, and developments. Int. J. Mol. Sci. https://doi.org/10.3390/ijms22062870 (2021).

  52. Navarro-Ledesma, S., Hamed-Hamed, D., Gonzalez-Munoz, A. & Pruimboom, L. Physical activity, insulin resistance and cancer: a systematic review. Cancers https://doi.org/10.3390/cancers16030656 (2024).

  53. Souza, J. et al. Physical-exercise-induced antioxidant effects on the brain and skeletal muscle. Antioxidants https://doi.org/10.3390/antiox11050826 (2022).

  54. Gomez-Cabrera, M. C., Domenech, E. & Vina, J. Moderate exercise is an antioxidant: upregulation of antioxidant genes by training. Free Radic. Biol. Med. 44, 126–131 (2008).

    Article  CAS  PubMed  Google Scholar 

  55. Scarfo, G., Daniele, S. & Franzoni, F. Antioxidant capability and physical exercise in neurobiology: a focus in neurodegeneration. Antioxidants https://doi.org/10.3390/antiox10020250 (2021).

  56. Scarfo, G. et al. Regular exercise delays microvascular endothelial dysfunction by regulating antioxidant capacity and cellular metabolism. Sci. Rep. 13, 17671 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Mousavi, S. R., Jafari, M., Rezaei, S., Agha-Alinejad, H. & Sobhani, V. Evaluation of the effects of different intensities of forced running wheel exercise on oxidative stress biomarkers in muscle, liver and serum of untrained rats. Lab. Anim. 49, 119–125 (2020).

    Article  Google Scholar 

  58. Liskiewicz, A. et al. Physical activity reduces anxiety and regulates brain fatty acid synthesis. Mol. Brain 13, 62 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. MoTrPAC Study Group, Lead Analysts & MoTrPAC Study GroupTemporal dynamics of the multi-omic response to endurance exercise training. Nature 629, 174–183 (2024).

    Article  Google Scholar 

  60. Franczyk, B., Gluba-Brzozka, A., Cialkowska-Rysz, A., Lawinski, J. & Rysz, J. The impact of aerobic exercise on HDL quantity and quality: a narrative review. Int. J. Mol. Sci. https://doi.org/10.3390/ijms24054653 (2023).

  61. Thomas, R., Kenfield, S. A., Yanagisawa, Y. & Newton, R. U. Why exercise has a crucial role in cancer prevention, risk reduction and improved outcomes. Br. Med. Bull. 139, 100–119 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Sheinboim, D. et al. An exercise-induced metabolic shield in distant organs blocks cancer progression and metastatic dissemination. Cancer Res. 82, 4164–4178 (2022). This work explores an interesting angle of the field exploring how exercise can help cancer outcomes both before and after diagnosis.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Lu, M. et al. Exercise inhibits tumor growth and central carbon metabolism in patient-derived xenograft models of colorectal cancer. Cancer Metab. 6, 14 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  64. Pedersen, L. et al. Voluntary running suppresses tumor growth through epinephrine- and IL-6-dependent NK cell mobilization and redistribution. Cell Metab. 23, 554–562 (2016).

    Article  CAS  PubMed  Google Scholar 

  65. Siqueira, I. R., Batabyal, R. A., Freishtat, R. & Cechinel, L. R. Potential involvement of circulating extracellular vesicles and particles on exercise effects in malignancies. Front. Endocrinol. 14, 1121390 (2023).

    Article  Google Scholar 

  66. Kurz, E. et al. Exercise-induced engagement of the IL-15/IL-15Rα axis promotes anti-tumor immunity in pancreatic cancer. Cancer Cell 40, 720–737.e5 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. McTiernan, A. Mechanisms linking physical activity with cancer. Nat. Rev. Cancer 8, 205–211 (2008).

    Article  CAS  PubMed  Google Scholar 

  68. Schmitz, K. H. et al. Exercise is medicine in oncology: engaging clinicians to help patients move through cancer. CA Cancer J. Clin. 69, 468–484 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  69. Guillerey, C., Huntington, N. D. & Smyth, M. J. Targeting natural killer cells in cancer immunotherapy. Nat. Immunol. 17, 1025–1036 (2016).

    Article  CAS  PubMed  Google Scholar 

  70. Waldmann, T. A. Interleukin-15 in the treatment of cancer. Expert. Rev. Clin. Immunol. 10, 1689–1701 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Steele, N. et al. A phase 1 trial of recombinant human IL-21 in combination with cetuximab in patients with metastatic colorectal cancer. Br. J. Cancer 106, 793–798 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Guo, Y., Xu, T., Chai, Y. & Chen, F. TGF-β signaling in progression of oral cancer. Int. J. Mol. Sci. https://doi.org/10.3390/ijms241210263 (2023).

  73. Lawrence, M. S. et al. Discovery and saturation analysis of cancer genes across 21 tumour types. Nature 505, 495–501 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Hoxhaj, G. & Manning, B. D. The PI3K-AKT network at the interface of oncogenic signalling and cancer metabolism. Nat. Rev. Cancer 20, 74–88 (2020).

    Article  CAS  PubMed  Google Scholar 

  75. Yu, M. et al. Development and safety of PI3K inhibitors in cancer. Arch. Toxicol. 97, 635–650 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Mayer, I. A. & Arteaga, C. L. The PI3K/AKT pathway as a target for cancer treatment. Annu. Rev. Med. 67, 11–28 (2016).

    Article  CAS  PubMed  Google Scholar 

  77. He, Y. et al. Targeting PI3K/Akt signal transduction for cancer therapy. Signal Transduct. Target. Ther. 6, 425 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Motzer, R. J. et al. Phase 3 trial of everolimus for metastatic renal cell carcinoma: final results and analysis of prognostic factors. Cancer 116, 4256–4265 (2010).

    Article  CAS  PubMed  Google Scholar 

  79. Janku, F., Yap, T. A. & Meric-Bernstam, F. Targeting the PI3K pathway in cancer: are we making headway? Nat. Rev. Clin. Oncol. 15, 273–291 (2018).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Goncalves, M. D., Hopkins, B. D. & Cantley, L. C. Phosphatidylinositol 3-kinase, growth disorders, and cancer. N. Engl. J. Med. 379, 2052–2062 (2018).

    Article  CAS  PubMed  Google Scholar 

  82. Hopkins, B. D. et al. Suppression of insulin feedback enhances the efficacy of PI3K inhibitors. Nature 560, 499–503 (2018). Despite promising pre-clinical results, PI3K inhibitors showed limited effectiveness in clinical trials. This work reveals mechanistic insights of PI3K signalling reactivation in tumours upon inhibition by insulin feedback, and it demonstrates that preventing this feedback through host systemic modulations significantly improves the efficacy of PI3K inhibitors.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Tannahill, G. M. et al. Succinate is an inflammatory signal that induces IL-1β through HIF-1α. Nature 496, 238–242 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Collins, N. et al. The bone marrow protects and optimizes immunological memory during dietary restriction. Cell 178, 1088–1101.e15 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Speakman, J. R. & Mitchell, S. E. Caloric restriction. Mol. Asp. Med. 32, 159–221 (2011).

    Article  CAS  Google Scholar 

  86. Forni, M. F. et al. Caloric restriction promotes structural and metabolic changes in the skin. Cell Rep. 20, 2678–2692 (2017).

    Article  CAS  PubMed  Google Scholar 

  87. Zhu, H. et al. Ketogenic diet for human diseases: the underlying mechanisms and potential for clinical implementations. Signal Transduct. Target. Ther. 7, 11 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  88. Weber, D. D. et al. Ketogenic diet in the treatment of cancer — where do we stand? Mol. Metab. 33, 102–121 (2020).

    Article  CAS  PubMed  Google Scholar 

  89. Massey, K. A. & Nicolaou, A. Lipidomics of polyunsaturated-fatty-acid-derived oxygenated metabolites. Biochem. Soc. Trans. 39, 1240–1246 (2011).

    Article  CAS  PubMed  Google Scholar 

  90. Yin, H., Xu, L. & Porter, N. A. Free radical lipid peroxidation: mechanisms and analysis. Chem. Rev. 111, 5944–5972 (2011).

    Article  CAS  PubMed  Google Scholar 

  91. Nair, J. et al. High dietary omega-6 polyunsaturated fatty acids drastically increase the formation of etheno-DNA base adducts in white blood cells of female subjects. Cancer Epidemiol. Biomark. Prev. 6, 597–601 (1997).

    CAS  Google Scholar 

  92. Little, C. & O’Brien, P. J. An intracellular GSH-peroxidase with a lipid peroxide substrate. Biochem. Biophys. Res. Commun. 31, 145–150 (1968).

    Article  CAS  PubMed  Google Scholar 

  93. Yang, W. S. et al. Regulation of ferroptotic cancer cell death by GPX4. Cell 156, 317–331 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Oliveira, C. L. P. et al. A nutritional perspective of ketogenic diet in cancer: a narrative review. J. Acad. Nutr. Diet. 118, 668–688 (2018).

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Chen, Y. et al. Metabolic intervention by low carbohydrate diet suppresses the onset and progression of neuroendocrine tumors. Cell Death Dis. 14, 597 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Lee, A. C. et al. Ras proteins induce senescence by altering the intracellular levels of reactive oxygen species. J. Biol. Chem. 274, 7936–7940 (1999).

    Article  CAS  PubMed  Google Scholar 

  98. Wei, S. J. et al. Ketogenic diet induces p53-dependent cellular senescence in multiple organs. Sci. Adv. 10, eado1463 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Su, Z., Liu, Y., Xia, Z., Rustgi, A. K. & Gu, W. An unexpected role for the ketogenic diet in triggering tumor metastasis by modulating BACH1-mediated transcription. Sci. Adv. 10, eadm9481 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Ferrer, M. et al. Ketogenic diet promotes tumor ferroptosis but induces relative corticosterone deficiency that accelerates cachexia. Cell Metab. 35, 1147–1162.e7 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Gao, X. et al. Dietary methionine influences therapy in mouse cancer models and alters human metabolism. Nature 572, 397–401 (2019). This work shows that a targeted dietary manipulation of an essential amino acid can specifically affect tumour–cell metabolism and enhance the effectiveness of chemotherapy and radiation therapies, providing mechanistic evidence of the opportunities for improvements using dietary interventions in combination with current treatments.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Chaturvedi, S., Hoffman, R. M. & Bertino, J. R. Exploiting methionine restriction for cancer treatment. Biochem. Pharmacol. 154, 170–173 (2018).

    Article  CAS  PubMed  Google Scholar 

  103. Badgley, M. A. et al. Cysteine depletion induces pancreatic tumor ferroptosis in mice. Science 368, 85–89 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Jain, M. et al. Metabolite profiling identifies a key role for glycine in rapid cancer cell proliferation. Science 336, 1040–1044 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Maddocks, O. D. et al. Serine starvation induces stress and p53-dependent metabolic remodelling in cancer cells. Nature 493, 542–546 (2013).

    Article  CAS  PubMed  Google Scholar 

  106. Maddocks, O. D. K. et al. Modulating the therapeutic response of tumours to dietary serine and glycine starvation. Nature 544, 372–376 (2017). This work shows that targeted dietary manipulation of non-essential amino acids can slow tumour growth, offering a potential therapeutic approach. However, it also highlights how genetic factors such as oncogenic activation can influence the response to dietary interventions.

    Article  CAS  PubMed  Google Scholar 

  107. Xiao, F. et al. Leucine deprivation inhibits proliferation and induces apoptosis of human breast cancer cells via fatty acid synthase. Oncotarget 7, 63679–63689 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  108. Leone, R. D. et al. Glutamine blockade induces divergent metabolic programs to overcome tumor immune evasion. Science 366, 1013–1021 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Ilerhunmwuwa, N. P. et al. Dietary interventions in cancer: a systematic review of all randomized controlled trials. J. Natl Cancer Inst. 116, 1026–1034 (2024).

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Piening, A. et al. Obesity-related T cell dysfunction impairs immunosurveillance and increases cancer risk. Nat. Commun. 15, 2835 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Dai, X. et al. Energy status dictates PD-L1 protein abundance and anti-tumor immunity to enable checkpoint blockade. Mol. Cell 81, 2317–2331.e16 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Ferrere, G. et al. Ketogenic diet and ketone bodies enhance the anticancer effects of PD-1 blockade. JCI Insight https://doi.org/10.1172/jci.insight.145207 (2021).

  115. Skrajnowska, D. & Bobrowska-Korczak, B. Role of zinc in immune system and anti-cancer defense mechanisms. Nutrients https://doi.org/10.3390/nu11102273 (2019).

  116. Stiles, L. I., Ferrao, K. & Mehta, K. J. Role of zinc in health and disease. Clin. Exp. Med. 24, 38 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Gao, H., Dai, W., Zhao, L., Min, J. & Wang, F. The role of zinc and zinc homeostasis in macrophage function. J. Immunol. Res. 2018, 6872621 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  118. Wessels, I., Haase, H., Engelhardt, G., Rink, L. & Uciechowski, P. Zinc deficiency induces production of the proinflammatory cytokines IL-1β and TNFα in promyeloid cells via epigenetic and redox-dependent mechanisms. J. Nutr. Biochem. 24, 289–297 (2013).

    Article  CAS  PubMed  Google Scholar 

  119. Fernandes, G. et al. Impairment of cell-mediated immunity functions by dietary zinc deficiency in mice. Proc. Natl Acad. Sci. USA 76, 457–461 (1979).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Dardenne, M., Pleau, J. M., Savino, W., Prasad, A. S. & Bach, J. F. Biochemical and biological aspects of the interaction between thymulin and zinc. Prog. Clin. Biol. Res. 380, 23–32 (1993).

    CAS  PubMed  Google Scholar 

  121. Lin, L. C. et al. Effects of zinc supplementation on clinical outcomes in patients receiving radiotherapy for head and neck cancers: a double-blinded randomized study. Int. J. Radiat. Oncol. Biol. Phys. 70, 368–373 (2008).

    Article  CAS  PubMed  Google Scholar 

  122. Lin, Y. S., Lin, L. C. & Lin, S. W. Effects of zinc supplementation on the survival of patients who received concomitant chemotherapy and radiotherapy for advanced nasopharyngeal carcinoma: follow-up of a double-blind randomized study with subgroup analysis. Laryngoscope 119, 1348–1352 (2009).

    Article  CAS  PubMed  Google Scholar 

  123. Prasad, A. S. Discovery of human zinc deficiency: its impact on human health and disease. Adv. Nutr. 4, 176–190 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Mocchegiani, E. et al. Zinc, metallothioneins and immunosenescence: effect of zinc supply as nutrigenomic approach. Biogerontology 12, 455–465 (2011).

    Article  CAS  PubMed  Google Scholar 

  125. Magrone, T., Pugliese, V., Fontana, S. & Jirillo, E. Human use of Leucoselect® Phytosome® with special reference to inflammatory-allergic pathologies in frail elderly patients. Curr. Pharm. Des. 20, 1011–1019 (2014).

    Article  CAS  PubMed  Google Scholar 

  126. Saito, Y. & Soga, T. Amino acid transporters as emerging therapeutic targets in cancer. Cancer Sci. 112, 2958–2965 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Lemos, H., Huang, L., Prendergast, G. C. & Mellor, A. L. Immune control by amino acid catabolism during tumorigenesis and therapy. Nat. Rev. Cancer 19, 162–175 (2019).

    Article  CAS  PubMed  Google Scholar 

  128. Czystowska-Kuzmicz, M. et al. Small extracellular vesicles containing arginase-1 suppress T-cell responses and promote tumor growth in ovarian carcinoma. Nat. Commun. 10, 3000 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  129. Ma, E. H. et al. Serine is an essential metabolite for effector T cell expansion. Cell Metab. 25, 345–357 (2017).

    Article  CAS  PubMed  Google Scholar 

  130. Rodriguez, P. C. et al. Regulation of T cell receptor CD3ζ chain expression by l-arginine. J. Biol. Chem. 277, 21123–21129 (2002).

    Article  CAS  PubMed  Google Scholar 

  131. Rodriguez, P. C., Quiceno, D. G. & Ochoa, A. C. l-Arginine availability regulates T-lymphocyte cell-cycle progression. Blood 109, 1568–1573 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Klysz, D. et al. Glutamine-dependent α-ketoglutarate production regulates the balance between T helper 1 cell and regulatory T cell generation. Sci. Signal. 8, ra97 (2015).

    Article  PubMed  Google Scholar 

  133. Lee, G. K. et al. Tryptophan deprivation sensitizes activated T cells to apoptosis prior to cell division. Immunology 107, 452–460 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Munn, D. H. et al. GCN2 kinase in T cells mediates proliferative arrest and anergy induction in response to indoleamine 2,3-dioxygenase. Immunity 22, 633–642 (2005).

    Article  CAS  PubMed  Google Scholar 

  135. Narsale, A. et al. Cancer-driven changes link T cell frequency to muscle strength in people with cancer: a pilot study. J. Cachexia Sarcopenia Muscle 10, 827–843 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  136. Bleve, A., Durante, B., Sica, A. & Consonni, F. M. Lipid metabolism and cancer immunotherapy: immunosuppressive myeloid cells at the crossroad. Int. J. Mol. Sci. https://doi.org/10.3390/ijms21165845 (2020).

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

    Article  CAS  PubMed  Google Scholar 

  138. Duncan, R. E., Ahmadian, M., Jaworski, K., Sarkadi-Nagy, E. & Sul, H. S. Regulation of lipolysis in adipocytes. Annu. Rev. Nutr. 27, 79–101 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Luo, W., Xu, Q., Wang, Q., Wu, H. & Hua, J. Effect of modulation of PPAR-γ activity on Kupffer cells M1/M2 polarization in the development of non-alcoholic fatty liver disease. Sci. Rep. 7, 44612 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  140. Catella, F. et al. Biosynthesis of P450 products of arachidonic acid in humans: increased formation in cardiovascular disease. Adv. Prostaglandin Thromboxane Leukot. Res. 21A, 193–196 (1991).

    CAS  PubMed  Google Scholar 

  141. Biswas, S. K. Metabolic reprogramming of immune cells in cancer progression. Immunity 43, 435–449 (2015).

    Article  CAS  PubMed  Google Scholar 

  142. Huang, S. C. et al. Cell-intrinsic lysosomal lipolysis is essential for alternative activation of macrophages. Nat. Immunol. 15, 846–855 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Odegaard, J. I. & Chawla, A. Alternative macrophage activation and metabolism. Annu. Rev. Pathol. 6, 275–297 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Hossain, F. et al. Inhibition of fatty acid oxidation modulates immunosuppressive functions of myeloid-derived suppressor cells and enhances cancer therapies. Cancer Immunol. Res. 3, 1236–1247 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. McQuade, J. L. et al. Association of body-mass index and outcomes in patients with metastatic melanoma treated with targeted therapy, immunotherapy, or chemotherapy: a retrospective, multicohort analysis. Lancet Oncol. 19, 310–322 (2018). In contrast to obesity effects in other contexts of cancer, this work demonstrates that obesity is associated with improved progression-free and overall survival in male patients with metastatic melanoma treated with targeted or immune therapies, highlighting the importance of understanding the molecular mechanisms linked to obesity in the context of the hosts.

    Article  PubMed  PubMed Central  Google Scholar 

  146. Albiges, L. et al. Body mass index and metastatic renal cell carcinoma: clinical and biological correlations. J. Clin. Oncol. 34, 3655–3663 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Wang, Z. et al. Paradoxical effects of obesity on T cell function during tumor progression and PD-1 checkpoint blockade. Nat. Med. 25, 141–151 (2019).

    Article  CAS  PubMed  Google Scholar 

  148. Wiig, H. & Swartz, M. A. Interstitial fluid and lymph formation and transport: physiological regulation and roles in inflammation and cancer. Physiol. Rev. 92, 1005–1060 (2012).

    Article  CAS  PubMed  Google Scholar 

  149. Jang, C. et al. Metabolite exchange between mammalian organs quantified in pigs. Cell Metab. 30, 594–606.e3 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  PubMed  PubMed Central  Google Scholar 

  151. Faubert, B. et al. Lactate metabolism in human lung tumors. Cell 171, 358–371.e9 (2017). This work reveals for the first time in infused non-small-cell lung cancer patients that lactate, not just glucose, serves as a major fuel source for the tricarboxylic acid cycle, highlighting a critical role for lactate in tumour metabolism beyond a waste metabolic product.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Tran, D. H. et al. De novo and salvage purine synthesis pathways across tissues and tumors. Cell 187, 3602–3618.e20 (2024).

    Article  CAS  PubMed  Google Scholar 

  153. Wu, Z. et al. Electron transport chain inhibition increases cellular dependence on purine transport and salvage. Cell Metab. 36, 1504–1520.e9 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Pavlides, S. et al. The reverse Warburg effect: aerobic glycolysis in cancer associated fibroblasts and the tumor stroma. Cell Cycle 8, 3984–4001 (2009).

    Article  CAS  PubMed  Google Scholar 

  155. Andersen, M. K. et al. Spatial differentiation of metabolism in prostate cancer tissue by MALDI-TOF MSI. Cancer Metab. 9, 9 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  156. Sun, C., Wang, F., Zhang, Y., Yu, J. & Wang, X. Mass spectrometry imaging-based metabolomics to visualize the spatially resolved reprogramming of carnitine metabolism in breast cancer. Theranostics 10, 7070–7082 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Kamphorst, J. J. et al. Human pancreatic cancer tumors are nutrient poor and tumor cells actively scavenge extracellular protein. Cancer Res. 75, 544–553 (2015). This work reveals a mechanism by which pancreatic tumours can take advantage of the host by scavenging extracellular proteins for amino acids, to sustain growth in poorly vascularized cancer.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Sousa, C. M. et al. Pancreatic stellate cells support tumour metabolism through autophagic alanine secretion. Nature 536, 479–483 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Auciello, F. R. et al. A stromal lysolipid-autotaxin signaling axis promotes pancreatic tumor progression. Cancer Discov. 9, 617–627 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Li, F. et al. FBP1 loss disrupts liver metabolism and promotes tumorigenesis through a hepatic stellate cell senescence secretome. Nat. Cell Biol. 22, 728–739 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  161. Martini, T., Naef, F. & Tchorz, J. S. Spatiotemporal metabolic liver zonation and consequences on pathophysiology. Annu. Rev. Pathol. 18, 439–466 (2023).

    Article  CAS  PubMed  Google Scholar 

  162. Coulouarn, C. et al. Hepatocyte-stellate cell cross-talk in the liver engenders a permissive inflammatory microenvironment that drives progression in hepatocellular carcinoma. Cancer Res. 72, 2533–2542 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Sherman, M. H. Stellate cells in tissue repair, inflammation, and cancer. Annu. Rev. Cell Dev. Biol. 34, 333–355 (2018).

    Article  CAS  PubMed  Google Scholar 

  164. Lyssiotis, C. A. & Kimmelman, A. C. Metabolic interactions in the tumor microenvironment. Trends Cell Biol. 27, 863–875 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Kerk, S. A. et al. Metabolic requirement for GOT2 in pancreatic cancer depends on environmental context. eLife https://doi.org/10.7554/eLife.73245 (2022).

  166. Attane, C. et al. Human bone marrow is comprised of adipocytes with specific lipid metabolism. Cell Rep. 30, 949–958.e6 (2020).

    Article  CAS  PubMed  Google Scholar 

  167. Panaroni, C. et al. Multiple myeloma cells induce lipolysis in adipocytes and uptake fatty acids through fatty acid transporter proteins. Blood 139, 876–888 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Shafat, M. S. et al. Leukemic blasts program bone marrow adipocytes to generate a protumoral microenvironment. Blood 129, 1320–1332 (2017).

    Article  CAS  PubMed  Google Scholar 

  169. Kumar, B. et al. Exosomes-driven lipolysis and bone marrow niche remodeling supports leukemia expansion. Haematologica 106, 1484–1488 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  170. Motohara, T. et al. An evolving story of the metastatic voyage of ovarian cancer cells: cellular and molecular orchestration of the adipose-rich metastatic microenvironment. Oncogene 38, 2885–2898 (2019).

    Article  CAS  PubMed  Google Scholar 

  171. Nieman, K. M. et al. Adipocytes promote ovarian cancer metastasis and provide energy for rapid tumor growth. Nat. Med. 17, 1498–1503 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Ladanyi, A. et al. Adipocyte-induced CD36 expression drives ovarian cancer progression and metastasis. Oncogene 37, 2285–2301 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Mukherjee, A. et al. Adipocytes reprogram cancer cell metabolism by diverting glucose towards glycerol-3-phosphate thereby promoting metastasis. Nat. Metab. 5, 1563–1577 (2023).

    Article  CAS  PubMed  Google Scholar 

  174. Wang, Y. Y. et al. Mammary adipocytes stimulate breast cancer invasion through metabolic remodeling of tumor cells. JCI Insight 2, e87489 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  175. Rossi, M. et al. PHGDH heterogeneity potentiates cancer cell dissemination and metastasis. Nature 605, 747–753 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Tasdogan, A. et al. Metabolic heterogeneity confers differences in melanoma metastatic potential. Nature 577, 115–120 (2020).

    Article  CAS  PubMed  Google Scholar 

  177. Gomes, A. P. et al. Altered propionate metabolism contributes to tumour progression and aggressiveness. Nat. Metab. 4, 435–443 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Mashimo, T. et al. Acetate is a bioenergetic substrate for human glioblastoma and brain metastases. Cell 159, 1603–1614 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. Neman, J. et al. Human breast cancer metastases to the brain display GABAergic properties in the neural niche. Proc. Natl Acad. Sci. USA 111, 984–989 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. Chen, J. et al. Gain of glucose-independent growth upon metastasis of breast cancer cells to the brain. Cancer Res. 75, 554–565 (2015).

    Article  CAS  PubMed  Google Scholar 

  181. Ngo, B. et al. Limited environmental serine and glycine confer brain metastasis sensitivity to PHGDH inhibition. Cancer Discov. 10, 1352–1373 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. Ferraro, G. B. et al. Fatty acid synthesis is required for breast cancer brain metastasis. Nat. Cancer 2, 414–428 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. Zou, Y. et al. Polyunsaturated fatty acids from astrocytes activate PPARγ signaling in cancer cells to promote brain metastasis. Cancer Discov. 9, 1720–1735 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. Parida, P. K. et al. Limiting mitochondrial plasticity by targeting DRP1 induces metabolic reprogramming and reduces breast cancer brain metastases. Nat. Cancer 4, 893–907 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. Jin, X. et al. A metastasis map of human cancer cell lines. Nature 588, 331–336 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  186. Savino, A. M. et al. Metabolic adaptation of acute lymphoblastic leukemia to the central nervous system microenvironment is dependent on stearoyl CoA desaturase. Nat. Cancer 1, 998–1009 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  187. Schwaiger-Haber, M. et al. Using mass spectrometry imaging to map fluxes quantitatively in the tumor ecosystem. Nat. Commun. 14, 2876 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  188. LeBleu, V. S. et al. PGC-1α mediates mitochondrial biogenesis and oxidative phosphorylation in cancer cells to promote metastasis. Nat. Cell Biol. 16, 992–1003 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. Ilter, D. et al. NADK-mediated de novo NADP(H) synthesis is a metabolic adaptation essential for breast cancer metastasis. Redox Biol. 61, 102627 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  190. Zhang, Y. et al. G6PD-mediated increase in de novo NADP+ biosynthesis promotes antioxidant defense and tumor metastasis. Sci. Adv. 8, eabo0404 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  191. Altea-Manzano, P. et al. A palmitate-rich metastatic niche enables metastasis growth via p65 acetylation resulting in pro-metastatic NF-κB signaling. Nat. Cancer 4, 344–364 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  192. Dupuy, F. et al. PDK1-dependent metabolic reprogramming dictates metastatic potential in breast cancer. Cell Metab. 22, 577–589 (2015).

    Article  CAS  PubMed  Google Scholar 

  193. Kietzmann, T. Metabolic zonation of the liver: the oxygen gradient revisited. Redox Biol. 11, 622–630 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  194. Bu, P. et al. Aldolase B-mediated fructose metabolism drives metabolic reprogramming of colon cancer liver metastasis. Cell Metab. 27, 1249–1262.e4 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  195. Yamaguchi, N. et al. PCK1 and DHODH drive colorectal cancer liver metastatic colonization and hypoxic growth by promoting nucleotide synthesis. eLife https://doi.org/10.7554/eLife.52135 (2019).

  196. Wu, Z. et al. TPO-induced metabolic reprogramming drives liver metastasis of colorectal cancer CD110+ tumor-initiating cells. Cell Stem Cell 17, 47–59 (2015).

    Article  CAS  PubMed  Google Scholar 

  197. Zhang, L. et al. Creatine promotes cancer metastasis through activation of Smad2/3. Cell Metab. 33, 1111–1123.e4 (2021).

    Article  CAS  PubMed  Google Scholar 

  198. Loo, J. M. et al. Extracellular metabolic energetics can promote cancer progression. Cell 160, 393–406 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  199. Journo, S. et al. Genomic alterations drive metastases formation in pancreatic ductal adenocarcinoma cancer: deciphering the role of CDKN2A and CDKN2B in mediating liver tropism. Oncogene 41, 1468–1481 (2022).

    Article  CAS  PubMed  Google Scholar 

  200. Choi, I. A., Umemoto, A., Mizuno, M. & Park-Min, K.-H. Bone metabolism — an underappreciated player. npj Metab. Health Dis. 2, 12 (2024).

    Article  Google Scholar 

  201. Tandon, M., Othman, A. H., Winogradzki, M. & Pratap, J. Bone metastatic breast cancer cells display downregulation of PKC-ζ with enhanced glutamine metabolism. Gene 775, 145419 (2021).

    Article  CAS  PubMed  Google Scholar 

  202. Krzeszinski, J. Y. et al. Lipid osteoclastokines regulate breast cancer bone metastasis. Endocrinology 158, 477–489 (2017).

    Article  CAS  PubMed  Google Scholar 

  203. Whitburn, J. et al. Metabolic profiling of prostate cancer in skeletal microenvironments identifies G6PD as a key mediator of growth and survival. Sci. Adv. 8, eabf9096 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  204. Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011).

    Article  CAS  PubMed  Google Scholar 

  205. Narsale, A. A. & Carson, J. A. Role of interleukin-6 in cachexia: therapeutic implications. Curr. Opin. Support. Palliat. Care 8, 321–327 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  206. Fujiwara, Y. et al. Indoleamine 2,3-dioxygenase (IDO) inhibitors and cancer immunotherapy. Cancer Treat. Rev. 110, 102461 (2022).

    Article  CAS  PubMed  Google Scholar 

  207. Munn, D. H. & Mellor, A. L. Indoleamine 2,3 dioxygenase and metabolic control of immune responses. Trends Immunol. 34, 137–143 (2013).

    Article  CAS  PubMed  Google Scholar 

  208. Lercher, A., Baazim, H. & Bergthaler, A. Systemic immunometabolism: challenges and opportunities. Immunity 53, 496–509 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  209. Dang, Q. et al. Cancer immunometabolism: advent, challenges, and perspective. Mol. Cancer 23, 72 (2024).

    Article  PubMed  PubMed Central  Google Scholar 

  210. Wang, Y. et al. Pre-metastatic niche: formation, characteristics and therapeutic implication. Signal Transduct. Target. Ther. 9, 236 (2024).

    Article  PubMed  PubMed Central  Google Scholar 

  211. Fong, M. Y. et al. Breast-cancer-secreted miR-122 reprograms glucose metabolism in premetastatic niche to promote metastasis. Nat. Cell Biol. 17, 183–194 (2015). This report shows that metabolites (glucose in this case) can be altered during the formation of the pre-metastatic niche, facilitating metastasis by altering the metabolism of local cells which increases nutrient availability to disseminated cancer cells in the niche.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  212. Li, P. et al. Lung mesenchymal cells elicit lipid storage in neutrophils that fuel breast cancer lung metastasis. Nat. Immunol. 21, 1444–1455 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  213. Gong, Z. et al. Lipid-laden lung mesenchymal cells foster breast cancer metastasis via metabolic reprogramming of tumor cells and natural killer cells. Cell Metab. 34, 1960–1976.e9 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  214. Kuhlmann-Hogan, A. et al. EGFR-driven lung adenocarcinomas co-opt alveolar macrophage metabolism and function to support EGFR signaling and growth. Cancer Discov. 14, 524–545 (2024).

  215. Ganguly, K. & Kimmelman, A. C. Reprogramming of tissue metabolism during cancer metastasis. Trends Cancer 9, 461–471 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  216. Fearon, K. et al. Definition and classification of cancer cachexia: an international consensus. Lancet Oncol. 12, 489–495 (2011).

    Article  PubMed  Google Scholar 

  217. Dhanapal, R., Saraswathi, T. & Rajkumar, N. Cancer cachexia. J. Oral Maxillofac. Pathol. 15, 257–260 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  218. von Haehling, S., Anker, M. S. & Anker, S. D. Prevalence and clinical impact of cachexia in chronic illness in Europe, USA, and Japan: facts and numbers update 2016. J. Cachexia Sarcopenia Muscle 7, 507–509 (2016).

    Article  Google Scholar 

  219. Baracos, V. E., Martin, L., Korc, M., Guttridge, D. C. & Fearon, K. C. H. Cancer-associated cachexia. Nat. Rev. Dis. Prim. 4, 17105 (2018).

    Article  PubMed  Google Scholar 

  220. Porporato, P. E. Understanding cachexia as a cancer metabolism syndrome. Oncogenesis 5, e200 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  221. Babic, A. et al. Adipose tissue and skeletal muscle wasting precede clinical diagnosis of pancreatic cancer. Nat. Commun. 14, 4317 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  222. Douglas, R. G. & Shaw, J. H. Metabolic effects of cancer. Br. J. Surg. 77, 246–254 (1990).

    Article  CAS  PubMed  Google Scholar 

  223. Donohoe, C. L., Ryan, A. M. & Reynolds, J. V. Cancer cachexia: mechanisms and clinical implications. Gastroenterol. Res. Pract. 2011, 601434 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  224. Fonseca, G., Farkas, J., Dora, E., von Haehling, S. & Lainscak, M. Cancer cachexia and related metabolic dysfunction. Int. J. Mol. Sci. https://doi.org/10.3390/ijms21072321 (2020).

  225. Flint, T. R. et al. Tumor-induced IL-6 reprograms host metabolism to suppress anti-tumor immunity. Cell Metab. 24, 672–684 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  226. Goncalves, M. D. et al. Fenofibrate prevents skeletal muscle loss in mice with lung cancer. Proc. Natl Acad. Sci. USA 115, E743–E752 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  227. Petruzzelli, M. & Wagner, E. F. Mechanisms of metabolic dysfunction in cancer-associated cachexia. Genes Dev. 30, 489–501 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  228. O’Connell, T. M. et al. Metabolic biomarkers for the early detection of cancer cachexia. Front. Cell Dev. Biol. 9, 720096 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  229. Wang, G. et al. Tumour extracellular vesicles and particles induce liver metabolic dysfunction. Nature 618, 374–382 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  230. Austin, J. & Marks, D. Hormonal regulators of appetite. Int. J. Pediatr. Endocrinol. 2009, 141753 (2009).

    Article  PubMed  Google Scholar 

  231. Yoo, E. S., Yu, J. & Sohn, J. W. Neuroendocrine control of appetite and metabolism. Exp. Mol. Med. 53, 505–516 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  232. Kim, K. S., Seeley, R. J. & Sandoval, D. A. Signalling from the periphery to the brain that regulates energy homeostasis. Nat. Rev. Neurosci. 19, 185–196 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  233. Lockhart, S. M., Saudek, V. & O’Rahilly, S. GDF15: a hormone conveying somatic distress to the brain. Endocr. Rev. https://doi.org/10.1210/endrev/bnaa007 (2020).

  234. Ni, J. & Zhang, L. Cancer cachexia: definition, staging, and emerging treatments. Cancer Manag. Res. 12, 5597–5605 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  235. Hart, B. L. Biological basis of the behavior of sick animals. Neurosci. Biobehav. Rev. 12, 123–137 (1988).

    Article  CAS  PubMed  Google Scholar 

  236. Fantino, M. & Wieteska, L. Evidence for a direct central anorectic effect of tumor-necrosis-factor-alpha in the rat. Physiol. Behav. 53, 477–483 (1993).

    Article  CAS  PubMed  Google Scholar 

  237. Scarlett, J. M. et al. Regulation of central melanocortin signaling by interleukin-1β. Endocrinology 148, 4217–4225 (2007).

    Article  CAS  PubMed  Google Scholar 

  238. Plata-Salaman, C. R., Sonti, G., Borkoski, J. P., Wilson, C. D. & French-Mullen, J. M. B. Anorexia induced by chronic central administration of cytokines at estimated pathophysiological concentrations. Physiol. Behav. 60, 867–875 (1996).

    Article  CAS  PubMed  Google Scholar 

  239. Kapas, L. & Krueger, J. M. Tumor necrosis factor-beta induces sleep, fever, and anorexia. Am. J. Physiol. 263, R703–R707 (1992).

    CAS  PubMed  Google Scholar 

  240. Sonti, G., Ilyin, S. E. & Plata-Salaman, C. R. Anorexia induced by cytokine interactions at pathophysiological concentrations. Am. J. Physiol. 270, R1394–R1402 (1996).

    CAS  PubMed  Google Scholar 

  241. Gayle, D., Ilyin, S. E. & Plata-Salaman, C. R. Central nervous system IL-1β system and neuropeptide Y mRNAs during IL-1β-induced anorexia in rats. Brain Res. Bull. 44, 311–317 (1997).

    Article  CAS  PubMed  Google Scholar 

  242. Wu, Q., Chen, J., Hua, T. & Cai, J. Alpha-melanocyte-stimulating hormone-mediated appetite regulation in the central nervous system. Neuroendocrinology 113, 885–904 (2023).

    Article  CAS  PubMed  Google Scholar 

  243. Cernackova, A., Tillinger, A., Bizik, J., Mravec, B. & Horvathova, L. Dynamics of cachexia-associated inflammatory changes in the brain accompanying intra-abdominal fibrosarcoma growth in Wistar rats. J. Neuroimmunol. 376, 578033 (2023).

    Article  CAS  PubMed  Google Scholar 

  244. Sun, Q. et al. Area postrema neurons mediate interleukin-6 function in cancer cachexia. Nat. Commun. 15, 4682 (2024). This work highlights the multisystemic nature of the mechanism leading to cachexia pathogenicity, involving central nervous system dysregulation by circulating IL-6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  245. Dodson, S. et al. Muscle wasting in cancer cachexia: clinical implications, diagnosis, and emerging treatment strategies. Annu. Rev. Med. 62, 265–279 (2011).

    Article  CAS  PubMed  Google Scholar 

  246. Gullett, N. P., Mazurak, V. C., Hebbar, G. & Ziegler, T. R. Nutritional interventions for cancer-induced cachexia. Curr. Probl. Cancer 35, 58–90 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  247. Mohan, A. et al. High prevalence of malnutrition and deranged relationship between energy demands and food intake in advanced non-small cell lung cancer. Eur. J. Cancer Care https://doi.org/10.1111/ecc.12503 (2017).

  248. Ohnuma, T. in Holland-Frei Cancer Medicine (BC Decker, 2003).

  249. Marceca, G. P., Londhe, P. & Calore, F. Management of cancer cachexia: attempting to develop new pharmacological agents for new effective therapeutic options. Front. Oncol. 10, 298 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  250. Prado, B. L. & Qian, Y. Anti-cytokines in the treatment of cancer cachexia. Ann. Palliat. Med. 8, 67–79 (2018).

    Article  PubMed  Google Scholar 

  251. Groarke, J. D. et al. Ponsegromab for the treatment of cancer cachexia. N. Engl. J. Med. https://doi.org/10.1056/NEJMoa2409515 (2024). This paper highlights the clinical implications of GDF-15 as a biomarker for cancer-associated cachexia and demonstrates that the inhibition of GDF-15 with ponsegromab increases weight gain and reduces cachexia symptoms.

  252. Yang, L., Shao, Y., Gao, T., Bajinka, O. & Yuan, X. Current advances in cancer energy metabolism under dietary restriction: a mini review. Med. Oncol. 41, 209 (2024).

    Article  PubMed  Google Scholar 

  253. Cormie, P., Zopf, E. M., Zhang, X. & Schmitz, K. H. The impact of exercise on cancer mortality, recurrence, and treatment-related adverse effects. Epidemiol. Rev. 39, 71–92 (2017).

    Article  PubMed  Google Scholar 

  254. Henriquez-Olguin, C. et al. Cytosolic ROS production by NADPH oxidase 2 regulates muscle glucose uptake during exercise. Nat. Commun. 10, 4623 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  255. Morville, T., Sahl, R. E., Moritz, T., Helge, J. W. & Clemmensen, C. Plasma metabolome profiling of resistance exercise and endurance exercise in humans. Cell Rep. 33, 108554 (2020).

    Article  CAS  PubMed  Google Scholar 

  256. Matsui, T., Soya, M. & Soya, H. Endurance and brain glycogen: a clue toward understanding central fatigue. Adv. Neurobiol. 23, 331–346 (2019).

    Article  PubMed  Google Scholar 

  257. Pagnotti, G. M. et al. Combating osteoporosis and obesity with exercise: leveraging cell mechanosensitivity. Nat. Rev. Endocrinol. 15, 339–355 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  258. Shao, M. et al. Advances in the research on myokine-driven regulation of bone metabolism. Heliyon 10, e22547 (2024).

    Article  PubMed  Google Scholar 

  259. Hensley, C. T. et al. Metabolic heterogeneity in human lung tumors. Cell 164, 681–694 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  260. Pisarsky, L. et al. Targeting metabolic symbiosis to overcome resistance to anti-angiogenic therapy. Cell Rep. 15, 1161–1174 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  261. Jimenez-Valerio, G. et al. Resistance to antiangiogenic therapies by metabolic symbiosis in renal cell carcinoma PDX models and patients. Cell Rep. 15, 1134–1143 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  262. Allen, E. et al. Metabolic symbiosis enables adaptive resistance to anti-angiogenic therapy that is dependent on mTOR Signaling. Cell Rep. 15, 1144–1160 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  263. Warburg, O., Wind, F. & Negelein, E. The metabolism of tumors in the body. J. Gen. Physiol. 8, 519–530 (1927).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  264. Cori, C. F. & Cori, G. T. The carbohydrate metabolism of tumors: II. Changes in the sugar, lactic acid, and CO2-combining power of blood passing through a tumor. J. Biochem. Chem. 65, 397–405 (1925).

    CAS  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  266. Liberti, M. V. & Locasale, J. W. The Warburg effect: how does it benefit cancer cells? Trends Biochem. Sci. 41, 211–218 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  267. Liu, Y. et al. An overview: the diversified role of mitochondria in cancer metabolism. Int. J. Biol. Sci. 19, 897–915 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  268. Wang, S. F., Tseng, L. M. & Lee, H. C. Role of mitochondrial alterations in human cancer progression and cancer immunity. J. Biomed. Sci. 30, 61 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  269. Fendt, S. M. 100 years of the Warburg effect: a cancer metabolism endeavor. Cell 187, 3824–3828 (2024).

    Article  CAS  PubMed  Google Scholar 

  270. Demicco, M., Liu, X. Z., Leithner, K. & Fendt, S. M. Metabolic heterogeneity in cancer. Nat. Metab. 6, 18–38 (2024).

    Article  PubMed  Google Scholar 

  271. Carr, A. C. & Maggini, S. Vitamin C and immune function. Nutrients https://doi.org/10.3390/nu9111211 (2017).

  272. Yoshii, K., Hosomi, K., Sawane, K. & Kunisawa, J. Metabolism of dietary and microbial vitamin B family in the regulation of host immunity. Front. Nutr. 6, 48 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  273. Ni, S., Yuan, Y., Kuang, Y. & Li, X. Iron metabolism and immune regulation. Front. Immunol. 13, 816282 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  274. Razaghi, A., Poorebrahim, M., Sarhan, D. & Björnstedt, M. Selenium stimulates the antitumour immunity: insights to future research. Eur. J. Cancer 155, 256–267 (2021).

    Article  CAS  PubMed  Google Scholar 

  275. Mora, J. R., Iwata, M. & von Andrian, U. H. Vitamin effects on the immune system: vitamins A and D take centre stage. Nat. Rev. Immunol. 8, 685–698 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  276. Shankar, A. H. & Prasad, A. S. Zinc and immune function: the biological basis of altered resistance to infection. Am. J. Clin. Nutr. 68, 447s–463s (1998).

    Article  CAS  PubMed  Google Scholar 

  277. Böttger, F., Vallés-Martí, A., Cahn, L. & Jimenez, C. R. High-dose intravenous vitamin C, a promising multi-targeting agent in the treatment of cancer. J. Exp. Clin. Cancer Res. 40, 343 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  278. Schoenfeld, J. D. et al. O2⋅− and H2O2-mediated disruption of Fe metabolism causes the differential susceptibility of NSCLC and GBM cancer cells to pharmacological ascorbate. Cancer Cell 31, 487–500.e8 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  279. Ou, J. et al. The safety and pharmacokinetics of high dose intravenous ascorbic acid synergy with modulated electrohyperthermia in Chinese patients with stage III-IV non-small cell lung cancer. Eur. J. Pharm. Sci. 109, 412–418 (2017).

    Article  CAS  PubMed  Google Scholar 

  280. US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/show/NCT02420314 (2024).

  281. US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/show/NCT02655913 (2018).

  282. Ma, Y. et al. High-dose parenteral ascorbate enhanced chemosensitivity of ovarian cancer and reduced toxicity of chemotherapy. Sci. Transl. Med. 6, 222ra218 (2014).

    Article  Google Scholar 

  283. US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/show/NCT00228319 (2018).

  284. Rothwell, P. M. et al. Short-term effects of daily aspirin on cancer incidence, mortality, and non-vascular death: analysis of the time course of risks and benefits in 51 randomised controlled trials. Lancet 379, 1602–1612 (2012).

    Article  CAS  PubMed  Google Scholar 

  285. Melhem-Bertrandt, A. et al. Beta-blocker use is associated with improved relapse-free survival in patients with triple-negative breast cancer. J. Clin. Oncol. 29, 2645–2652 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  286. Singhal, S. et al. Antitumor activity of thalidomide in refractory multiple myeloma. N. Engl. J. Med. 341, 1565–1571 (1999).

    Article  CAS  PubMed  Google Scholar 

  287. Barnard, R. A. et al. Autophagy inhibition delays early but not late-stage metastatic disease. J. Pharmacol. Exp. Ther. 358, 282–293 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  288. Zeh, H. J. et al. A randomized phase II preoperative study of autophagy inhibition with high-dose hydroxychloroquine and gemcitabine/Nab-paclitaxel in pancreatic cancer patients. Clin. Cancer Res. 26, 3126–3134 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  289. Pollak, M. Metformin and other biguanides in oncology: advancing the research agenda. Cancer Prev. Res. 3, 1060–1065 (2010).

    Article  CAS  Google Scholar 

  290. Bosetti, C. et al. Cancer risk for patients using thiazolidinediones for type 2 diabetes: a meta-analysis. Oncologist 18, 148–156 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  291. Meloni, A. R., DeYoung, M. B., Lowe, C. & Parkes, D. G. GLP-1 receptor activated insulin secretion from pancreatic β-cells: mechanism and glucose dependence. Diabetes Obes. Metab. 15, 15–27 (2013).

    Article  CAS  PubMed  Google Scholar 

  292. Carlessi, R. et al. GLP-1 receptor signalling promotes β-cell glucose metabolism via mTOR-dependent HIF-1α activation. Sci. Rep. 7, 2661 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  293. Raven, L. M., Stoita, A., Feller, R. B., Brown, C. & Greenfield, J. R. Delayed gastric emptying with perioperative use of glucagon-like peptide-1 receptor agonists. Am. J. Med. 136, e233–e234 (2023).

    Article  CAS  PubMed  Google Scholar 

  294. Nakatani, Y. et al. Effect of GLP-1 receptor agonist on gastrointestinal tract motility and residue rates as evaluated by capsule endoscopy. Diabetes Metab. 43, 430–437 (2017).

    Article  CAS  PubMed  Google Scholar 

  295. Shah, M. & Vella, A. Effects of GLP-1 on appetite and weight. Rev. Endocr. Metab. Disord. 15, 181–187 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  296. Wang, L., Wang, W., Kaelber, D. C., Xu, R. & Berger, N. A. GLP-1 receptor agonists and colorectal cancer risk in drug-naive patients with type 2 diabetes, with and without overweight/obesity. JAMA Oncol. 10, 256–258 (2024). This paper shows that GLP-1 receptor agonists can be used for weight loss, as their usage has exploded in popularity in recent years,but there is undoubtedly a wealth of information still to be discovered about their potential role in other diseases such as cancer.

    Article  PubMed  Google Scholar 

  297. De Barra, C. et al. Glucagon-like peptide-1 therapy in people with obesity restores natural killer cell metabolism and effector function. Obesity 31, 1787–1797 (2023).

    Article  PubMed  Google Scholar 

  298. Wolf, N. K., Kissiov, D. U. & Raulet, D. H. Roles of natural killer cells in immunity to cancer, and applications to immunotherapy. Nat. Rev. Immunol. 23, 90–105 (2023).

    Article  CAS  PubMed  Google Scholar 

  299. Michelet, X. et al. Metabolic reprogramming of natural killer cells in obesity limits antitumor responses. Nat. Immunol. 19, 1330–1340 (2018).

    Article  CAS  PubMed  Google Scholar 

  300. O’Brien, K. L. & Finlay, D. K. Immunometabolism and natural killer cell responses. Nat. Rev. Immunol. 19, 282–290 (2019).

    Article  PubMed  Google Scholar 

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Acknowledgements

P.A.-M. is supported by the European Research Council Starting Grant (101116912) and the Ramón y Cajal Program. A.D.-F. is funded by Cancer Center Scholar T32 Grant (20910820). T.J. is supported by research grants from the National Institutes of Health (1R37CA286477-01A1, 1OT2CA278690-03), the Cancer Research Institute (CGCATF-2021/100019), the Mark Foundation (20-028-EDV), the STARR Cancer Consortium (I15-0037), and the Simons Foundation (1142664). A.E. is supported by research grants from Minerva, Israel Ministry of Health, the European Research Council (PoC 101111915), the Israel Science Foundation (873/23), and The Israel Cancer Research Fund (837124). A.E. is the incumbent of the Sir Ernst B. Chain Professorial Chair. The Moross Integrated Cancer Center, EKARD Institute for Cancer Diagnosis Research, Abisch-Frenkel RNA Therapeutics Center, G. S. Omenn and M. A. Darling, and the Koret Foundation generously supported the research performed by A.E.’s laboratory. Grammarly and ChatGPT were used for English editing.

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  1. These authors contributed equally: Patricia Altea-Manzano, Amanda Decker-Farrell.

Authors and Affiliations

  1. Andalusian Molecular Biology and Regenerative Medicine Centre-CSIC, Sevilla, Spain

    Patricia Altea-Manzano

  2. Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA

    Amanda Decker-Farrell & Tobias Janowitz

  3. Weizmann Institute of Science, Rehovot, Israel

    Ayelet Erez

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The authors contributed equally to all aspects of the article.

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Correspondence to Patricia Altea-Manzano or Ayelet Erez.

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T.J. received consultancy fees from LepTx and Flagship Pioneering, not related to this manuscript. A.E. shares patent rights with the startup companies OnVagus and MetaboCure. The other authors declare no competing interests.

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Glossary

Agouti-related peptide (AgRP) neurons

Specialized neurons within the hypothalamus that modulate food intake and energy expenditure through recognition of AgRP levels.

Cachexia

A complex metabolic syndrome often associated with end-stage cancer that is characterized by severe weight loss, muscle atrophy, fatigue, weakness and loss of appetite, and the condition is not reversible by nutritional support alone.

Caloric restriction

A dietary regimen that reduces calorie intake without incurring malnutrition, which has been associated with lifespan extension and reduced incidence of age-related diseases in some animal models.

Fatty acid activation

The process by which fatty acids are converted into fatty acyl-CoA molecules, making them metabolically active and ready for subsequent reactions.

Ferroptosis

Iron-dependent form of regulated cell death caused by excessive accumulation of ROS and oxidative damage to membrane lipids, leading to loss of membrane integrity.

Glucagon-like peptide-1

(GLP-1). A hormone primarily produced in the intestine, pancreas and brain that is implicated in insulin production, glucagon suppression, gastric emptying and satiety.

Ketogenic diet

A high-fat, low-carbohydrate diet that induces a metabolic state known as ketosis, wherein the body relies on ketone bodies for energy instead of glucose.

Ketone bodies

Water-soluble molecules (acetoacetate, β-hydroxybutyrate and acetone) produced from fatty acids in the liver that can serve as an alternative energy source, particularly for the brain, during low food intake, carbohydrate-restricted diets, starvation or prolonged intense exercise.

Lipid peroxidation

A process in which free radicals steal electrons from the lipids in cell membranes, resulting in cell damage. This oxidative degradation of lipids is a key mechanism of cell injury and is implicated in various diseases, including cancer.

Liver zonation

The spatial heterogeneity of metabolic processes in the liver, wherein different zones (periportal, midzonal and perivenous) perform distinct metabolic functions to efficiently regulate various physiological processes, such as detoxification, glucose production, and ammonia metabolism.

Metabolic dysfunction-associated steatotic liver disease

(MASLD). A liver disease previously known as non-alcoholic fatty liver disease that is associated with metabolic dysfunction and characterized by excess fat accumulation in the liver.

Metabolic symbiosis

A cooperative interaction between different types of cells within a tumour and its microenvironment, wherein they exchange metabolites to support cancer growth and survival under conditions of metabolic stress, such as hypoxia or nutrient scarcity.

Metabolic syndrome

A cluster of conditions — including increased blood pressure, high blood sugar levels, excess body fat around the waist, and abnormal cholesterol levels — that occur together, increasing the risk of heart disease, stroke and type 2 diabetes.

Metastatic tropism

The tendency of cancer cells to preferentially metastasize to specific organs, which is influenced by factors such as the organ metabolic environment, the expression of specific receptors on cancer cells, and the production of chemokines by target organs.

Pro-opiomelanocortin (POMC) neurons

Specialized neurons within the hypothalamus that monitor global energy balance and control appetite through recognition of POMC levels.

Reactive oxygen species

(ROS). Chemically reactive molecules containing oxygen, such as peroxides and superoxides, that have roles in cell signalling and homeostasis and, if excessively produced, can lead to oxidative stress and cellular damage, thereby contributing to ageing and diseases such as cancer.

Sarcopenia

The progressive loss of muscle mass and strength owing to normal ageing.

Senescent cells

Cells that have irreversibly stopped dividing and entered a metabolically active survival state in response to cellular stress or as a consequence of ageing.

Tumour macroenvironment

The broader physiological environment in which a tumour exists, extending beyond the immediate tumour microenvironment, encompassing the surrounding tissues, organs, immune system and systemic factors in the body, such as hormones, cytokines and nutrients, that can influence tumour growth and progression.

Tumour microenvironment

(TME). The complex ecosystem surrounding and influencing a tumour, which includes cellular and non-cellular components, such as fibroblasts, immune cells, endothelia, nutrients, extracellular matrix, and nutrients.

Warburg effect

A metabolic shift that supports rapid cell growth and proliferation in which cancer cells predominantly produce energy by anaerobic glycolysis rather than oxidative phosphorylation, even when oxygen is abundant, leading to lactic acid fermentation in the cytosol.

Western diet

Dietary pattern characterized by high intakes of saturated fats, refined sugars, processed foods and low consumption of fibre, fruits, vegetables and whole grains, which is often linked to nutrient imbalances.

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Altea-Manzano, P., Decker-Farrell, A., Janowitz, T. et al. Metabolic interplays between the tumour and the host shape the tumour macroenvironment. Nat Rev Cancer (2025). https://doi.org/10.1038/s41568-024-00786-4

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