Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Cancer cell metabolism and antitumour immunity

An Author Correction to this article was published on 28 May 2024

This article has been updated

Abstract

Accumulating evidence suggests that metabolic rewiring in malignant cells supports tumour progression not only by providing cancer cells with increased proliferative potential and an improved ability to adapt to adverse microenvironmental conditions but also by favouring the evasion of natural and therapy-driven antitumour immune responses. Here, we review cancer cell-intrinsic and cancer cell-extrinsic mechanisms through which alterations of metabolism in malignant cells interfere with innate and adaptive immune functions in support of accelerated disease progression. Further, we discuss the potential of targeting such alterations to enhance anticancer immunity for therapeutic purposes.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Effects of glucose, lactate and the TCA cycle on anticancer immunity.
Fig. 2: Effects of fatty acid and eicosanoid metabolism on anticancer immunity.
Fig. 3: Effects of nucleotide and amino acid metabolism on anticancer immunity.

Similar content being viewed by others

Change history

References

  1. Hanahan, D. Hallmarks of cancer: new dimensions. Cancer Discov. 12, 31–46 (2022).

    Article  CAS  PubMed  Google Scholar 

  2. Izzo, L. T., Affronti, H. C. & Wellen, K. E. The bidirectional relationship between cancer epigenetics and metabolism. Annu. Rev. Cancer Biol. 5, 235–257 (2021).

    Article  PubMed  Google Scholar 

  3. Pirozzi, C. J. & Yan, H. The implications of IDH mutations for cancer development and therapy. Nat. Rev. Clin. Oncol. 18, 645–661 (2021).

    Article  CAS  PubMed  Google Scholar 

  4. Kerk, S. A., Papagiannakopoulos, T., Shah, Y. M. & Lyssiotis, C. A. Metabolic networks in mutant KRAS-driven tumours: tissue specificities and the microenvironment. Nat. Rev. Cancer 21, 510–525 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Kruiswijk, F., Labuschagne, C. F. & Vousden, K. H. p53 in survival, death and metabolic health: a lifeguard with a licence to kill. Nat. Rev. Mol. Cell Biol. 16, 393–405 (2015).

    Article  CAS  PubMed  Google Scholar 

  6. Vitale, I., Shema, E., Loi, S. & Galluzzi, L. Intratumoral heterogeneity in cancer progression and response to immunotherapy. Nat. Med. 27, 212–224 (2021).

    Article  CAS  PubMed  Google Scholar 

  7. Singleton, D. C., Macann, A. & Wilson, W. R. Therapeutic targeting of the hypoxic tumour microenvironment. Nat. Rev. Clin. Oncol. 18, 751–772 (2021).

    Article  PubMed  Google Scholar 

  8. Petroni, G., Buqué, A., Coussens, L. M. & Galluzzi, L. Targeting oncogene and non-oncogene addiction to inflame the tumour microenvironment. Nat. Rev. Drug. Discov. 21, 440–462 (2022).

    Article  CAS  PubMed  Google Scholar 

  9. Stine, Z. E., Schug, Z. T., Salvino, J. M. & Dang, C. V. Targeting cancer metabolism in the era of precision oncology. Nat. Rev. Drug. Discov. 21, 141–162 (2022).

    Article  CAS  PubMed  Google Scholar 

  10. Warburg, O., Posener, K. & Negelein, E. Über den stoffwechsel der carcinomzelle [German]. Naturwissenschaften 12, 1131–1137 (1924).

    Article  CAS  Google Scholar 

  11. Debnath, J., Gammoh, N. & Ryan, K. M. Autophagy and autophagy-related pathways in cancer. Nat. Rev. Mol. Cell Biol. 24, 560–575 (2023).

    Article  CAS  PubMed  Google Scholar 

  12. Kim, J. & DeBerardinis, R. J. Mechanisms and implications of metabolic heterogeneity in cancer. Cell Metab. 30, 434–446 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Kroemer, G., Chan, T. A., Eggermont, A. M. M. & Galluzzi, L. Immunosurveillance in clinical cancer management. CA Cancer J. Clin. 74, 187–202 (2024).

    Article  PubMed  Google Scholar 

  14. Klapp, V. et al. The DNA damage response and inflammation in cancer. Cancer Discov. 13, 1521–1545 (2023).

    Article  CAS  PubMed  Google Scholar 

  15. Kroemer, G., Galassi, C., Zitvogel, L. & Galluzzi, L. Immunogenic cell stress and death. Nat. Immunol. 23, 487–500 (2022).

    Article  CAS  PubMed  Google Scholar 

  16. Voss, K. et al. A guide to interrogating immunometabolism. Nat. Rev. Immunol. 21, 637–652 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Bantug, G. R. & Hess, C. The immunometabolic ecosystem in cancer. Nat. Immunol. 24, 2008–2020 (2023).

    Article  CAS  PubMed  Google Scholar 

  18. Leone, R. D. & Powell, J. D. Metabolism of immune cells in cancer. Nat. Rev. Cancer 20, 516–531 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Lunt, S. Y. & Vander Heiden, M. G. Aerobic glycolysis: meeting the metabolic requirements of cell proliferation. Annu. Rev. Cell Dev. Biol. 27, 441–464 (2011).

    Article  CAS  PubMed  Google Scholar 

  20. Chang, C. H. et al. Metabolic competition in the tumor microenvironment is a driver of cancer progression. Cell 162, 1229–1241 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Reinfeld, B. I. et al. Cell-programmed nutrient partitioning in the tumour microenvironment. Nature 593, 282–288 (2021). This article elegantly shows that intratumoural myeloid cells have increased glucose uptake compared with malignant cells.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Cascone, T. et al. Increased tumor glycolysis characterizes immune resistance to adoptive T cell therapy. Cell Metab. 27, 977–987.e4 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Guo, D. et al. Aerobic glycolysis promotes tumor immune evasion by hexokinase2-mediated phosphorylation of IκBα. Cell Metab. 34, 1312–1324.e6 (2022).

    Article  CAS  PubMed  Google Scholar 

  24. Li, W. et al. Aerobic glycolysis controls myeloid-derived suppressor cells and tumor immunity via a specific CEBPB isoform in triple-negative breast cancer. Cell Metab. 28, 87–103.e6 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Wu, L. et al. Tumor aerobic glycolysis confers immune evasion through modulating sensitivity to T cell-mediated bystander killing via TNF-α. Cell Metab. 35, 1580–1596.e9 (2023).

    Article  CAS  PubMed  Google Scholar 

  26. Galluzzi, L., Kepp, O., Vander Heiden, M. G. & Kroemer, G. Metabolic targets for cancer therapy. Nat. Rev. Drug. Discov. 12, 829–846 (2013).

    Article  CAS  PubMed  Google Scholar 

  27. Claps, G. et al. The multiple roles of LDH in cancer. Nat. Rev. Clin. Oncol. 19, 749–762 (2022).

    Article  PubMed  Google Scholar 

  28. Elia, I. et al. Tumor cells dictate anti-tumor immune responses by altering pyruvate utilization and succinate signaling in CD8+ T cells. Cell Metab. 34, 1137–1150.e6 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Quinn, W. J. et al. Lactate limits T cell proliferation via the NAD(H) redox state. Cell Rep. 33, 108500 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Ma, J. et al. Lithium carbonate revitalizes tumor-reactive CD8+ T cells by shunting lactic acid into mitochondria. Nat. Immunol. 25, 552–561 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Brand, A. et al. LDHA-associated lactic acid production blunts tumor immunosurveillance by T and NK cells. Cell Metab. 24, 657–671 (2016).

    Article  CAS  PubMed  Google Scholar 

  32. Oshima, N. et al. Dynamic imaging of LDH inhibition in tumors reveals rapid in vivo metabolic rewiring and vulnerability to combination therapy. Cell Rep. 30, 1798–1810.e4 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Rundqvist, H. et al. Cytotoxic T-cells mediate exercise-induced reductions in tumor growth. eLife 9, e59996 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Feng, Q. et al. Lactate increases stemness of CD8+ T cells to augment anti-tumor immunity. Nat. Commun. 13, 4981 (2022). This report shows that lactate may mediate immunostimulatory effects by promoting CD8+ T cell stemness.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Angelin, A. et al. Foxp3 reprograms T cell metabolism to function in low-glucose, high-lactate environments. Cell Metab. 25, 1282–1293.e7 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Kumagai, S. et al. Lactic acid promotes PD-1 expression in regulatory T cells in highly glycolytic tumor microenvironments. Cancer Cell 40, 201–218.e9 (2022).

    Article  CAS  PubMed  Google Scholar 

  37. Watson, M. J. et al. Metabolic support of tumour-infiltrating regulatory T cells by lactic acid. Nature 591, 645–651 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Gu, J. et al. Tumor metabolite lactate promotes tumorigenesis by modulating MOESIN lactylation and enhancing TGF-β signaling in regulatory T cells. Cell Rep. 39, 110986 (2022).

    Article  CAS  PubMed  Google Scholar 

  39. Xiong, J. et al. Lactylation-driven METTL3-mediated RNA m6A modification promotes immunosuppression of tumor-infiltrating myeloid cells. Mol. Cell 82, 1660–1677.e10 (2022).

    Article  CAS  PubMed  Google Scholar 

  40. Zappasodi, R. et al. CTLA-4 blockade drives loss of Treg stability in glycolysis-low tumours. Nature 591, 652–658 (2021). This work is the first demonstration that CTLA4 blockers are particularly effective at destabilizing Treg cells in tumours with limited glycolytic activity.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Chen, P. et al. Gpr132 sensing of lactate mediates tumor–macrophage interplay to promote breast cancer metastasis. Proc. Natl Acad. Sci. USA 114, 580–585 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Qian, Y. et al. MCT4-dependent lactate secretion suppresses antitumor immunity in LKB1-deficient lung adenocarcinoma. Cancer Cell 41, 1363–1380.e7 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Pittet, M. J., Michielin, O. & Migliorini, D. Clinical relevance of tumour-associated macrophages. Nat. Rev. Clin. Oncol. 19, 402–421 (2022).

    Article  PubMed  Google Scholar 

  44. Pietrocola, F., Galluzzi, L., Bravo-San Pedro, J. M., Madeo, F. & Kroemer, G. Acetyl coenzyme A: a central metabolite and second messenger. Cell Metab. 21, 805–821 (2015).

    Article  CAS  PubMed  Google Scholar 

  45. Sullivan, L. B., Gui, D. Y. & Vander Heiden, M. G. Altered metabolite levels in cancer: implications for tumour biology and cancer therapy. Nat. Rev. Cancer 16, 680–693 (2016).

    Article  CAS  PubMed  Google Scholar 

  46. Cheng, J. et al. Cancer-cell-derived fumarate suppresses the anti-tumor capacity of CD8+ T cells in the tumor microenvironment. Cell Metab. 35, 961–978.e10 (2023).

    Article  CAS  PubMed  Google Scholar 

  47. Zecchini, V. et al. Fumarate induces vesicular release of mtDNA to drive innate immunity. Nature 615, 499–506 (2023). This article elegantly shows that the accumulation of fumarate as elicited by mutation of fumarate hydratase causes mitochondrial disruption coupled with cGAS activation.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Li, J. et al. Non-cell-autonomous cancer progression from chromosomal instability. Nature 620, 1080–1088 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Vanpouille-Box, C., Demaria, S., Formenti, S. C. & Galluzzi, L. Cytosolic DNA sensing in organismal tumor control. Cancer Cell 34, 361–378 (2018).

    Article  CAS  PubMed  Google Scholar 

  50. Mangalhara, K. C. et al. Manipulating mitochondrial electron flow enhances tumor immunogenicity. Science 381, 1316–1323 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Gomez, V. et al. Breast cancer-associated macrophages promote tumorigenesis by suppressing succinate dehydrogenase in tumor cells. Sci. Signal 13, eaax4585 (2020).

    Article  CAS  PubMed  Google Scholar 

  52. Notarangelo, G. et al. Oncometabolite d-2HG alters T cell metabolism to impair CD8+ T cell function. Science 377, 1519–1529 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Bunse, L. et al. Suppression of antitumor T cell immunity by the oncometabolite (R)-2-hydroxyglutarate. Nat. Med. 24, 1192–1203 (2018). Together with Notarangelo et al. (2022), this work provides mechanistic insights into the ability of the oncometabolite D-2HG to mediate robust immunosuppressive effects.

    Article  CAS  PubMed  Google Scholar 

  54. Minogue, E. et al. Glutarate regulates T cell metabolism and anti-tumour immunity. Nat. Metab. 5, 1747–1764 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Miller, K. D. et al. Acetate acts as a metabolic immunomodulator by bolstering T-cell effector function and potentiating antitumor immunity in breast cancer. Nat. Cancer 4, 1491–1507 (2023).

    Article  CAS  PubMed  Google Scholar 

  56. Bachem, A. et al. Microbiota-derived short-chain fatty acids promote the memory potential of antigen-activated CD8+ T cells. Immunity 51, 285–297.e5 (2019).

    Article  CAS  PubMed  Google Scholar 

  57. Ryan, D. G. et al. Coupling Krebs cycle metabolites to signalling in immunity and cancer. Nat. Metab. 1, 16–33 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Zhao, H. et al. Myeloid-derived itaconate suppresses cytotoxic CD8+ T cells and promotes tumour growth. Nat. Metab. 4, 1660–1673 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Olagnier, D. et al. Nrf2 negatively regulates STING indicating a link between antiviral sensing and metabolic reprogramming. Nat. Commun. 9, 3506 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  60. Hoy, A. J., Nagarajan, S. R. & Butler, L. M. Tumour fatty acid metabolism in the context of therapy resistance and obesity. Nat. Rev. Cancer 21, 753–766 (2021).

    Article  CAS  PubMed  Google Scholar 

  61. Duman, C. et al. Acyl-CoA-binding protein drives glioblastoma tumorigenesis by sustaining fatty acid oxidation. Cell Metab. 30, 274–289.e5 (2019).

    Article  CAS  PubMed  Google Scholar 

  62. Jiang, N. et al. Fatty acid oxidation fuels glioblastoma radioresistance with CD47-mediated immune evasion. Nat. Commun. 13, 1511 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Mariño, G. et al. Regulation of autophagy by cytosolic acetyl-coenzyme A. Mol. Cell 53, 710–725 (2014).

    Article  PubMed  Google Scholar 

  64. Liu, Z. et al. CPT1A-mediated fatty acid oxidation confers cancer cell resistance to immune-mediated cytolytic killing. Proc. Natl Acad. Sci. USA 120, e2302878120 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Harel, M. et al. Proteomics of melanoma response to immunotherapy reveals mitochondrial dependence. Cell 179, 236–250.e18 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Luo, J., Yang, H. & Song, B. L. Mechanisms and regulation of cholesterol homeostasis. Nat. Rev. Mol. Cell Biol. 21, 225–245 (2020).

    Article  CAS  PubMed  Google Scholar 

  67. Anderson, H. A., Hiltbold, E. M. & Roche, P. A. Concentration of MHC class II molecules in lipid rafts facilitates antigen presentation. Nat. Immunol. 1, 156–162 (2000).

    Article  CAS  PubMed  Google Scholar 

  68. Bi, K. et al. Antigen-induced translocation of PKC-θ to membrane rafts is required for T cell activation. Nat. Immunol. 2, 556–563 (2001).

    Article  CAS  PubMed  Google Scholar 

  69. Wang, G. et al. Arf1-mediated lipid metabolism sustains cancer cells and its ablation induces anti-tumor immune responses in mice. Nat. Commun. 11, 220 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Röhrig, F. & Schulze, A. The multifaceted roles of fatty acid synthesis in cancer. Nat. Rev. Cancer 16, 732–749 (2016).

    Article  PubMed  Google Scholar 

  71. Xu, S. et al. Uptake of oxidized lipids by the scavenger receptor CD36 promotes lipid peroxidation and dysfunction in CD8+ T cells in tumors. Immunity 54, 1561–1577.e7 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Ma, X. et al. CD36-mediated ferroptosis dampens intratumoral CD8+ T cell effector function and impairs their antitumor ability. Cell Metab. 33, 1001–1012.e5 (2021). Together with Xu et al. (2021), this work implicates the uptake of oxidized lipids by CD8+ T cells via the scavenger receptor CD36 in the establishment of intratumoural immunosuppression.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Jiang, L., Fang, X., Wang, H., Li, D. & Wang, X. Ovarian cancer-intrinsic fatty acid synthase prevents anti-tumor immunity by disrupting tumor-infiltrating dendritic cells. Front. Immunol. 9, 2927 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Wang, H. et al. CD36-mediated metabolic adaptation supports regulatory T cell survival and function in tumors. Nat. Immunol. 21, 298–308 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  75. Ao, Y. Q. et al. Tumor-infiltrating CD36+CD8+ T cells determine exhausted tumor microenvironment and correlate with inferior response to chemotherapy in non-small cell lung cancer. BMC Cancer 23, 367 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Accioly, M. T. et al. Lipid bodies are reservoirs of cyclooxygenase-2 and sites of prostaglandin-E2 synthesis in colon cancer cells. Cancer Res. 68, 1732–1740 (2008).

    Article  CAS  PubMed  Google Scholar 

  77. Huang, Q. et al. Caspase 3-mediated stimulation of tumor cell repopulation during cancer radiotherapy. Nat. Med. 17, 860–866 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Zelenay, S. et al. Cyclooxygenase-dependent tumor growth through evasion of immunity. Cell 162, 1257–1270 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Bayerl, F. et al. Tumor-derived prostaglandin E2 programs cDC1 dysfunction to impair intratumoral orchestration of anti-cancer T cell responses. Immunity 56, 1341–1358.e11 (2023).

    Article  CAS  PubMed  Google Scholar 

  80. Bottcher, J. P. et al. NK cells stimulate recruitment of cDC1 into the tumor microenvironment promoting cancer immune control. Cell 172, 1022–1037.e14 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Wei, J. et al. The COX-2–PGE2 pathway promotes tumor evasion in colorectal adenomas. Cancer Prev. Res. 15, 285–296 (2022).

    Article  CAS  Google Scholar 

  82. Goto, S. et al. Upregulation of PD-L1 expression by prostaglandin E2 and the enhancement of IFN-γ by anti-PD-L1 antibody combined with a COX-2 inhibitor in Mycoplasma bovis infection. Front. Vet. Sci. 7, 12 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  83. Sajiki, Y. et al. Prostaglandin E2-induced immune exhaustion and enhancement of antiviral effects by anti-PD-L1 antibody combined with COX-2 inhibitor in bovine leukemia virus infection. J. Immunol. 203, 1313–1324 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Sarkar, O. S. et al. Monocytic MDSCs exhibit superior immune suppression via adenosine and depletion of adenosine improves efficacy of immunotherapy. Sci. Adv. 9, eadg3736 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Zhang, B. et al. MFSD2A potentiates gastric cancer response to anti-PD-1 immunotherapy by reprogramming the tumor microenvironment to activate T cell response. Cancer Commun. 43, 1097–1116 (2023).

    Article  Google Scholar 

  86. Mullen, N. J. & Singh, P. K. Nucleotide metabolism: a pan-cancer metabolic dependency. Nat. Rev. Cancer 23, 275–294 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Lee, J. S. et al. Urea cycle dysregulation generates clinically relevant genomic and biochemical signatures. Cell 174, 1559–1570.e22 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Elliott, M. R. et al. Nucleotides released by apoptotic cells act as a find-me signal to promote phagocytic clearance. Nature 461, 282–286 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Chekeni, F. B. et al. Pannexin 1 channels mediate ‘find-me’ signal release and membrane permeability during apoptosis. Nature 467, 863–867 (2010). Together with Elliott et al. (2009), this report is the first to document the ability of extracellular nucleotides including ATP to function as chemoattractants for myeloid cells.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Ma, Y. et al. Anticancer chemotherapy-induced intratumoral recruitment and differentiation of antigen-presenting cells. Immunity 38, 729–741 (2013).

    Article  CAS  PubMed  Google Scholar 

  91. Ghiringhelli, F. et al. Activation of the NLRP3 inflammasome in dendritic cells induces IL-1β-dependent adaptive immunity against tumors. Nat. Med. 15, 1170–1178 (2009).

    Article  CAS  PubMed  Google Scholar 

  92. Thompson, E. A. & Powell, J. D. Inhibition of the adenosine pathway to potentiate cancer immunotherapy: potential for combinatorial approaches. Annu. Rev. Med. 72, 331–348 (2021).

    Article  CAS  PubMed  Google Scholar 

  93. Kepp, O. et al. ATP and cancer immunosurveillance. EMBO J. 40, e108130 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Edwards, D. N. et al. Selective glutamine metabolism inhibition in tumor cells improves antitumor T lymphocyte activity in triple-negative breast cancer. J. Clin. Invest. 131, e140100 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Leone, R. D. et al. Glutamine blockade induces divergent metabolic programs to overcome tumor immune evasion. Science 366, 1013–1021 (2019). This article elegantly shows that pharmacological inhibition of glutaminase in the TME can robustly impair cancer cell metabolism while sparing CD8+ T cells.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Oh, M. H. et al. Targeting glutamine metabolism enhances tumor-specific immunity by modulating suppressive myeloid cells. J. Clin. Invest. 130, 3865–3884 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Guo, C. et al. SLC38A2 and glutamine signalling in cDC1s dictate anti-tumour immunity. Nature 620, 200–208 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Wang, Z. et al. Metabolic control of CD47 expression through LAT2-mediated amino acid uptake promotes tumor immune evasion. Nat. Commun. 13, 6308 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Sanderson, S. M., Gao, X., Dai, Z. & Locasale, J. W. Methionine metabolism in health and cancer: a nexus of diet and precision medicine. Nat. Rev. Cancer 19, 625–637 (2019).

    Article  CAS  PubMed  Google Scholar 

  101. Hung, M. H. et al. Tumor methionine metabolism drives T-cell exhaustion in hepatocellular carcinoma. Nat. Commun. 12, 1455 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Fang, L. et al. Methionine restriction promotes cGAS activation and chromatin untethering through demethylation to enhance antitumor immunity. Cancer Cell 41, 1118–1133.e12 (2023).

    Article  CAS  PubMed  Google Scholar 

  103. Bian, Y. et al. Cancer SLC43A2 alters T cell methionine metabolism and histone methylation. Nature 585, 277–282 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Huang, Y. et al. A bimetallic nanoplatform for STING activation and CRISPR/Cas mediated depletion of the methionine transporter in cancer cells restores anti-tumor immune responses. Nat. Commun. 14, 4647 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Xue, Y. et al. Intermittent dietary methionine deprivation facilitates tumoral ferroptosis and synergizes with checkpoint blockade. Nat. Commun. 14, 4758 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Xue, C. et al. Tryptophan metabolism in health and disease. Cell Metab. 35, 1304–1326 (2023).

    Article  CAS  PubMed  Google Scholar 

  107. Fallarino, F. et al. T cell apoptosis by tryptophan catabolism. Cell Death Differ. 9, 1069–1077 (2002).

    Article  CAS  PubMed  Google Scholar 

  108. Chen, W., Liang, X., Peterson, A. J., Munn, D. H. & Blazar, B. R. The indoleamine 2,3-dioxygenase pathway is essential for human plasmacytoid dendritic cell-induced adaptive T regulatory cell generation. J. Immunol. 181, 5396–5404 (2008).

    Article  CAS  PubMed  Google Scholar 

  109. Sonner, J. K. et al. The stress kinase GCN2 does not mediate suppression of antitumor T cell responses by tryptophan catabolism in experimental melanomas. Oncoimmunology 5, e1240858 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  110. Munn, D. H. et al. Inhibition of T cell proliferation by macrophage tryptophan catabolism. J. Exp. Med. 189, 1363–1372 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Kesarwani, P. et al. Quinolinate promotes macrophage-induced immune tolerance in glioblastoma through the NMDAR/PPARγ signaling axis. Nat. Commun. 14, 1459 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Yuan, H. et al. Lysine catabolism reprograms tumour immunity through histone crotonylation. Nature 617, 818–826 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Lemberg, K. M., Gori, S. S., Tsukamoto, T., Rais, R. & Slusher, B. S. Clinical development of metabolic inhibitors for oncology. J. Clin. Invest. 132, e148550 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  114. Galluzzi, L., Humeau, J., Buque, A., Zitvogel, L. & Kroemer, G. Immunostimulation with chemotherapy in the era of immune checkpoint inhibitors. Nat. Rev. Clin. Oncol. 17, 725–741 (2020).

    Article  PubMed  Google Scholar 

  115. Petroni, G., Buque, A., Zitvogel, L., Kroemer, G. & Galluzzi, L. Immunomodulation by targeted anticancer agents. Cancer Cell 39, 310–345 (2021).

    Article  CAS  PubMed  Google Scholar 

  116. Galluzzi, L., Aryankalayil, M. J., Coleman, C. N. & Formenti, S. C. Emerging evidence for adapting radiotherapy to immunotherapy. Nat. Rev. Clin. Oncol. 20, 543–557 (2023).

    Article  PubMed  Google Scholar 

  117. Zheng, J. B. et al. Glucose metabolism inhibitor PFK-015 combined with immune checkpoint inhibitor is an effective treatment regimen in cancer. Oncoimmunology 11, 2079182 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  118. Redman, R. A., Pohlmann, P. R., Kurman, M. R., Tapolsky, G. & Chesney, J. A. A phase I, dose-escalation, multi-center study of PFK-158 in patients with advanced solid malignancies explores a first-in-man inhbibitor of glycolysis. J. Clin. Oncol. 33, TPS2606 (2015).

    Article  Google Scholar 

  119. Halford, S. et al. A phase I dose-escalation study of AZD3965, an oral monocarboxylate transporter 1 inhibitor, in patients with advanced cancer. Clin. Cancer Res. 29, 1429–1439 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Babl, N. et al. MCT4 blockade increases the efficacy of immune checkpoint blockade. J. Immunother. Cancer 11, e007349 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  121. Lopez, E. et al. Inhibition of lactate transport by MCT-1 blockade improves chimeric antigen receptor T-cell therapy against B-cell malignancies. J. Immunother. Cancer 11, e006287 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  122. Rodriguez-Ruiz, M. E., Vitale, I., Harrington, K. J., Melero, I. & Galluzzi, L. Immunological impact of cell death signaling driven by radiation on the tumor microenvironment. Nat. Immunol. 21, 120–134 (2020).

    Article  CAS  PubMed  Google Scholar 

  123. Cytlak, U. M. et al. Immunomodulation by radiotherapy in tumour control and normal tissue toxicity. Nat. Rev. Immunol. 22, 124–138 (2022).

    Article  CAS  PubMed  Google Scholar 

  124. Wicker, C. A. et al. Glutaminase inhibition with telaglenastat (CB-839) improves treatment response in combination with ionizing radiation in head and neck squamous cell carcinoma models. Cancer Lett. 502, 180–188 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Boysen, G. et al. Glutaminase inhibitor CB-839 increases radiation sensitivity of lung tumor cells and human lung tumor xenografts in mice. Int. J. Radiat. Biol. 95, 436–442 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Varghese, S. et al. The glutaminase inhibitor CB-839 (Telaglenastat) enhances the antimelanoma activity of T-cell-mediated immunotherapies. Mol. Cancer Ther. 20, 500–511 (2021).

    Article  CAS  PubMed  Google Scholar 

  127. Lee, C. H. et al. Telaglenastat plus everolimus in advanced renal cell carcinoma: a randomized, double-blinded, placebo-controlled, phase II ENTRATA trial. Clin. Cancer Res. 28, 3248–3255 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Meric-Bernstam, F. et al. Telaglenastat plus cabozantinib or everolimus for advanced or metastatic renal cell carcinoma: an open-label phase I trial. Clin. Cancer Res. 28, 1540–1548 (2022).

    Article  CAS  PubMed  Google Scholar 

  129. Tannir, N. M. et al. Efficacy and safety of telaglenastat plus cabozantinib vs placebo plus cabozantinib in patients with advanced renal cell carcinoma: the CANTATA randomized clinical trial. JAMA Oncol. 8, 1411–1418 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  130. Byun, J. K. et al. Inhibition of glutamine utilization synergizes with immune checkpoint inhibitor to promote antitumor immunity. Mol. Cell 80, 592–606.e8 (2020).

    Article  CAS  PubMed  Google Scholar 

  131. Vitale, I. et al. Apoptotic cell death in disease-current understanding of the NCCD 2023. Cell Death Differ. 30, 1097–1154 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  132. Platten, M., Nollen, E. A. A., Rohrig, U. F., Fallarino, F. & Opitz, C. A. Tryptophan metabolism as a common therapeutic target in cancer, neurodegeneration and beyond. Nat. Rev. Drug. Discov. 18, 379–401 (2019).

    Article  CAS  PubMed  Google Scholar 

  133. Kraehenbuehl, L., Weng, C. H., Eghbali, S., Wolchok, J. D. & Merghoub, T. Enhancing immunotherapy in cancer by targeting emerging immunomodulatory pathways. Nat. Rev. Clin. Oncol. 19, 37–50 (2022).

    Article  CAS  PubMed  Google Scholar 

  134. Jochems, C. et al. The IDO1 selective inhibitor epacadostat enhances dendritic cell immunogenicity and lytic ability of tumor antigen-specific T cells. Oncotarget 7, 37762–37772 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  135. Mitchell, T. C. et al. Epacadostat plus pembrolizumab in patients with advanced solid tumors: phase I results from a multicenter, open-label phase I/II trial (ECHO-202/KEYNOTE-037). J. Clin. Oncol. 36, 3223–3230 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Long, G. V. et al. Epacadostat plus pembrolizumab versus placebo plus pembrolizumab in patients with unresectable or metastatic melanoma (ECHO-301/KEYNOTE-252): a phase 3, randomised, double-blind study. Lancet Oncol. 20, 1083–1097 (2019).

    Article  CAS  PubMed  Google Scholar 

  137. Clement, C. C. et al. 3-Hydroxy-l-kynurenamine is an immunomodulatory biogenic amine. Nat. Commun. 12, 4447 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. [No authors listed]. Companies scaling back IDO1 inhibitor trials. Cancer Discov. 8, Of5 (2018).

  139. Shi, D. et al. USP14 promotes tryptophan metabolism and immune suppression by stabilizing IDO1 in colorectal cancer. Nat. Commun. 13, 5644 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Michaud, M. et al. Autophagy-dependent anticancer immune responses induced by chemotherapeutic agents in mice. Science 334, 1573–1577 (2011). This study reports the first demonstration that pre-mortem autophagic responses are essential for the release of ATP by dying cancer cells.

    Article  CAS  PubMed  Google Scholar 

  141. Ohta, A. et al. A2A adenosine receptor protects tumors from antitumor T cells. Proc. Natl Acad. Sci. USA 103, 13132–13137 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Young, A. et al. Co-inhibition of CD73 and A2AR adenosine signaling improves anti-tumor immune responses. Cancer Cell 30, 391–403 (2016).

    Article  CAS  PubMed  Google Scholar 

  143. Tang, T. et al. Transcriptional control of pancreatic cancer immunosuppression by metabolic enzyme CD73 in a tumor-autonomous and -autocrine manner. Nat. Commun. 14, 3364 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Wennerberg, E. et al. CD73 blockade promotes dendritic cell infiltration of irradiated tumors and tumor rejection. Cancer Immunol. Res. 8, 465–478 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Beavis, P. A. et al. Targeting the adenosine 2A receptor enhances chimeric antigen receptor T cell efficacy. J. Clin. Invest. 127, 929–941 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  146. Beavis, P. A. et al. Adenosine receptor 2A blockade increases the efficacy of anti-PD-1 through enhanced antitumor T-cell responses. Cancer Immunol. Res. 3, 506–517 (2015).

    Article  CAS  PubMed  Google Scholar 

  147. Mittal, D. et al. Antimetastatic effects of blocking PD-1 and the adenosine A2A receptor. Cancer Res. 74, 3652–3658 (2014).

    Article  CAS  PubMed  Google Scholar 

  148. Chiappori, A. A. et al. Phase I study of taminadenant (PBF509/NIR178), an adenosine 2A receptor antagonist, with or without spartalizumab (PDR001), in patients with advanced non-small cell lung cancer. Clin. Cancer Res. 28, 2313–2320 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Lim, E. A. et al. Phase Ia/b, open-label, multicenter study of AZD4635 (an adenosine A2A receptor antagonist) as monotherapy or combined with durvalumab, in patients with solid tumors. Clin. Cancer Res. 28, 4871–4884 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Cascone, T. et al. Neoadjuvant durvalumab alone or combined with novel immuno-oncology agents in resectable lung cancer: the phase II NeoCOAST platform trial. Cancer Discov. 13, 2394–2411 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Herbst, R. S. et al. COAST: an open-label, phase II, multidrug platform study of durvalumab alone or in combination with oleclumab or monalizumab in patients with unresectable, stage III non-small-cell lung cancer. J. Clin. Oncol. 40, 3383–3393 (2022).

    Article  CAS  PubMed  Google Scholar 

  152. Falchook, G. et al. First-in-human study of the safety, pharmacokinetics, and pharmacodynamics of first-in-class fatty acid synthase inhibitor TVB-2640 alone and with a taxane in advanced tumors. EClinicalMedicine 34, 100797 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  153. Kelly, W. et al. Phase II investigation of TVB-2640 (denifanstat) with bevacizumab in patients with first relapse high-grade astrocytoma. Clin. Cancer Res. 29, 2419–2425 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Tang, R. et al. Targeting neoadjuvant chemotherapy-induced metabolic reprogramming in pancreatic cancer promotes anti-tumor immunity and chemo-response. Cell Rep. Med. 4, 101234 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Francica, B. J. et al. Dual blockade of EP2 and EP4 signaling is required for optimal immune activation and antitumor activity against prostaglandin-expressing tumors. Cancer Res. Commun. 3, 1486–1500 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Wang, Y. et al. Combination of EP4 antagonist MF-766 and anti-PD-1 promotes anti-tumor efficacy by modulating both lymphocytes and myeloid cells. Oncoimmunology 10, 1896643 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  157. Chen, J. S. et al. CC-01 (chidamide plus celecoxib) modifies the tumor immune microenvironment and reduces tumor progression combined with immune checkpoint inhibitor. Sci. Rep. 12, 1100 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Chan, J. P. et al. The lysolipid transporter Mfsd2a regulates lipogenesis in the developing brain. PLoS Biol. 16, e2006443 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  159. Boergesen, M. et al. Genome-wide profiling of liver X receptor, retinoid X receptor, and peroxisome proliferator-activated receptor α in mouse liver reveals extensive sharing of binding sites. Mol. Cell Biol. 32, 852–867 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Hou, Y. et al. SMPDL3A is a cGAMP-degrading enzyme induced by LXR-mediated lipid metabolism to restrict cGAS-STING DNA sensing. Immunity 56, 2492–2507.e10 (2023).

    Article  CAS  PubMed  Google Scholar 

  161. Dai, J. et al. Acetylation blocks cGAS activity and inhibits self-DNA-induced autoimmunity. Cell 176, 1447–1460.e14 (2019). This report documents the ability of aspirin to block cGAS signalling by non-enzymatic acetylation.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Arber, N. et al. Celecoxib for the prevention of colorectal adenomatous polyps. N. Engl. J. Med. 355, 885–895 (2006).

    Article  CAS  PubMed  Google Scholar 

  163. Mitchell, M. J. et al. Engineering precision nanoparticles for drug delivery. Nat. Rev. Drug. Discov. 20, 101–124 (2021).

    Article  CAS  PubMed  Google Scholar 

  164. De Martino, M. et al. Radiation therapy promotes unsaturated fatty acids to maintain survival of glioblastoma. Cancer Lett. 570, 216329 (2023).

    Article  PubMed  Google Scholar 

  165. Dagogo-Jack, I. & Shaw, A. T. Tumour heterogeneity and resistance to cancer therapies. Nat. Rev. Clin. Oncol. 15, 81–94 (2018).

    Article  CAS  PubMed  Google Scholar 

  166. Gengenbacher, N., Singhal, M. & Augustin, H. G. Preclinical mouse solid tumour models: status quo, challenges and perspectives. Nat. Rev. Cancer 17, 751–765 (2017).

    Article  CAS  PubMed  Google Scholar 

  167. Chuprin, J. et al. Humanized mouse models for immuno-oncology research. Nat. Rev. Clin. Oncol. 20, 192–206 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  168. Park, J., Morley, T. S., Kim, M., Clegg, D. J. & Scherer, P. E. Obesity and cancer — mechanisms underlying tumour progression and recurrence. Nat. Rev. Endocrinol. 10, 455–465 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Sepich-Poore, G. D. et al. The microbiome and human cancer. Science 371, eabc4552 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Mishra, R. et al. Stromal epigenetic alterations drive metabolic and neuroendocrine prostate cancer reprogramming. J. Clin. Invest. 128, 4472–4484 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  172. Sousa, C. M. et al. Erratum: pancreatic stellate cells support tumour metabolism through autophagic alanine secretion. Nature 540, 150 (2016).

    Article  CAS  PubMed  Google Scholar 

  173. Olivares, O. et al. Collagen-derived proline promotes pancreatic ductal adenocarcinoma cell survival under nutrient limited conditions. Nat. Commun. 8, 16031 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Schwörer, S. et al. Proline biosynthesis is a vent for TGFβ-induced mitochondrial redox stress. EMBO J. 39, e103334 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  175. 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 

  176. Lee, P., Chandel, N. S. & Simon, M. C. Cellular adaptation to hypoxia through hypoxia inducible factors and beyond. Nat. Rev. Mol. Cell Biol. 21, 268–283 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Terme, M. et al. VEGFA–VEGFR pathway blockade inhibits tumor-induced regulatory T-cell proliferation in colorectal cancer. Cancer Res. 73, 539–549 (2013).

    Article  CAS  PubMed  Google Scholar 

  178. Allard, B., Allard, D., Buisseret, L. & Stagg, J. The adenosine pathway in immuno-oncology. Nat. Rev. Clin. Oncol. 17, 611–629 (2020).

    Article  CAS  PubMed  Google Scholar 

  179. Vignali, P. D. A. et al. Hypoxia drives CD39-dependent suppressor function in exhausted T cells to limit antitumor immunity. Nat. Immunol. 24, 267–279 (2023).

    Article  CAS  PubMed  Google Scholar 

  180. Sattiraju, A. et al. Hypoxic niches attract and sequester tumor-associated macrophages and cytotoxic T cells and reprogram them for immunosuppression. Immunity 56, 1825–1843.e6 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. Park, J. H. et al. Tumor hypoxia represses γδ T cell-mediated antitumor immunity against brain tumors. Nat. Immunol. 22, 336–346 (2021).

    Article  CAS  PubMed  Google Scholar 

  182. Klionsky, D. J. et al. Autophagy in major human diseases. EMBO J. 40, e108863 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. Clarke, A. J. & Simon, A. K. Autophagy in the renewal, differentiation and homeostasis of immune cells. Nat. Rev. Immunol. 19, 170–183 (2019).

    Article  CAS  PubMed  Google Scholar 

  184. Yamazaki, T. et al. Mitochondrial DNA drives abscopal responses to radiation that are inhibited by autophagy. Nat. Immunol. 21, 1160–1171 (2020).

    Article  CAS  PubMed  Google Scholar 

  185. Poillet-Perez, L. et al. Autophagy promotes growth of tumors with high mutational burden by inhibiting a T-cell immune response. Nat. Cancer 1, 923–934 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  186. Yamamoto, K. et al. Autophagy promotes immune evasion of pancreatic cancer by degrading MHC-I. Nature 581, 100–105 (2020). Together with Yamazaki et al. (2020) and Poillet-Perez et al. (2020), this work documents various mechanisms by which autophagic responses in malignant cells mediate robust immunosuppressive effects.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  187. Baginska, J. et al. Granzyme B degradation by autophagy decreases tumor cell susceptibility to natural killer-mediated lysis under hypoxia. Proc. Natl Acad. Sci. USA 110, 17450–17455 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  188. Galluzzi, L., Bravo-San Pedro, J. M., Levine, B., Green, D. R. & Kroemer, G. Pharmacological modulation of autophagy: therapeutic potential and persisting obstacles. Nat. Rev. Drug. Discov. 16, 487–511 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. Levy, J. M. M., Towers, C. G. & Thorburn, A. Targeting autophagy in cancer. Nat. Rev. Cancer 17, 528–542 (2017).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

M.D.M. is supported by the Future Leaders 2023 Postdoctoral Fellowship from the Brain Tumour Charity (#BTC224874-01). J.C.R. receives support related to this work from an R01 grant from the National Institutes of Health National Cancer Institute (NIH/NCI) (#CA217987). Among other funds, L.G. is/has been supported by an R01 grant from the NIH/NCI (#CA271915) and two Breakthrough Level 2 grants from the US Department of Defense (DoD) Breast Cancer Research Program (BCRP) (#BC180476P1, #BC210945). Among other funds, C.V.-B. is supported by an R01 grant from the NHI National Institute of Neurological Disorders and Stroke (NIH/NINDS) (#NS131945-01) and an R21 grant from the NIH/NCI (#CA280787-01).

Author information

Authors and Affiliations

Authors

Contributions

C.V.-B. and L.G. conceived the article. M.D.M., C.V.-B. and L.G. wrote the first version of the manuscript with constructive input from J.C.R. M.D.M. prepared display items under supervision from C.V.-B. and L.G. All authors approved the submitted version of the article.

Corresponding authors

Correspondence to Lorenzo Galluzzi or Claire Vanpouille-Box.

Ethics declarations

Competing interests

J.C.R. is a founder and scientific advisory board member of Sitryx Therapeutics. L.G. is/has been holding research contracts with Lytix Biopharma, Promontory and Onxeo; has received consulting/advisory honoraria from Boehringer Ingelheim, AstraZeneca, OmniSEQ, Onxeo, The Longevity Labs, Inzen, Imvax, Sotio, Promontory, Noxopharm, EduCom and the Luke Heller TECPR2 Foundation; and holds Promontory stock options. The other authors declare no competing interests.

Peer review

Peer review information

Nature Reviews Immunology thanks C. Dang and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Glossary

Anabolism

A set of metabolic pathways that build large molecules from smaller units in support of cell growth and proliferation.

Autophagy

A lysosome-dependent catabolic pathway that ensures the degradation of supernumerary, dysfunctional or potentially cytotoxic cytoplasmic material.

Cancer-associated fibroblasts

(CAFs). A heterogeneous population of fibroblasts that define the tumour stroma and communicate with both malignant and immune components of the tumour microenvironment.

Catabolism

A set of metabolic pathways that break down large molecules into smaller units for recycling or for the production of ATP.

Crotonylation

The post-translational modification of lysine residues by crotonyl-CoA.

De novo lipid biosynthesis

A metabolic cascade converting acetyl-CoA into long-chain lipids for cellular anabolism.

Immune checkpoint inhibitors

(ICIs). Monoclonal antibodies targeting co-inhibitory T cell receptors in support of restored anticancer immunosurveillance.

Lactylation

The post-translational modification of lysine residues by lactate.

Myeloid-derived suppressor cells

(MDSCs). Poorly differentiated myeloid cells with prominent immunosuppressive and tumour-promoting properties.

Oxidative phosphorylation

(OXPHOS). A mitochondrial pathway, fed by NADH and succinate provided by the tricarboxylic acid cycle (TCA cycle), that generates ATP from a series of oxidation reactions that culminate with the generation of H2O.

Pentose phosphate pathway

A metabolic shunt that diverts glycolytic intermediates towards the synthesis of nucleotides, some amino acids and antioxidants.

T cell exhaustion

A state of T cell dysfunction that arises during many chronic infections and cancer.

Tricarboxylic acid cycle

(TCA cycle). A mitochondrial circuit that ensures adequate levels of key metabolites involved in several catabolic and anabolic reactions, including acetyl-CoA, pyruvate, oxaloacetate, succinate and α-ketoglutarate.

Tumour-associated macrophages

(TAMs). A heterogeneous and plastic population of intratumoural macrophages with a spectrum of activity ranging from prominently antitumour (so-called M1-like TAMs) to prominently pro-tumour (so-called M2-like TAMs). Caution should be made when extrapolating these in vitro-defined M1 and M2 phenotypes to in vivo settings.

Urea cycle

A metabolic pathway to convert excess ammonia into urea for excretion.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

De Martino, M., Rathmell, J.C., Galluzzi, L. et al. Cancer cell metabolism and antitumour immunity. Nat Rev Immunol 24, 654–669 (2024). https://doi.org/10.1038/s41577-024-01026-4

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41577-024-01026-4

This article is cited by

Search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer