Abstract
The depletion or accumulation of metabolites in the tumour microenvironment is one of the hallmarks of cancer, but targeting cancer cell metabolism therapeutically must also take into account the impact on metabolic pathways in immune cells. As we understand more about immunometabolism, opportunities arise for synergies between agents that modulate metabolism and immunotherapy. In this Review, we discuss the pivotal role of metabolic pathways in both cancer and immune cells in shaping the tumour microenvironment. We survey major anabolic and catabolic pathways and discuss how metabolic modulators and dietary nutrients can improve the anticancer immune response and overcome drug resistance mechanisms. Agents in the clinic include inhibitors of the adenosine and tryptophan pathways, and we discuss opportunities and challenges for successful drug development in the context of immune checkpoint blockade and chimeric antigen receptor (CAR)-T cell therapies.
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Acknowledgements
This study was supported by the Bavarian Cancer Research Center (BZKF) (TANGO to S.K.), the Deutsche Forschungsgemeinschaft (DFG, KO5055/3-1 to S.K.), Marie Sklodowska-Curie Training Network for Optimizing Adoptive T Cell Therapy of Cancer (funded by the Horizon 2020 programme of the European Union; grant 955575 to S.K.), Marie Sklodowska-Curie Training Network for tracking and controlling therapeutic immune cells in cancer (funded by the Horizon Programme of the EU, grant 101168810 to S.K.), Else Kröner-Fresenius-Stiftung (IOLIN to S.K.), German Cancer Aid (AvantCAR.de to S.K.), the Wilhelm-Sander-Stiftung (to S. K.), the Go-Bio-Initiative (to S.K.), the m4-Award of the Bavarian Ministry for Economic Affairs (to S.K.), Bundesministerium für Bildung und Forschung (to S.K.), European Research Council (CoG 101124203 to S.K., MSCA Fellowship 101106951 to M.P.T.), by the SFB-TRR 338/1 2021-452881907 (to S.K.), Fritz-Bender Foundation (to S.K.), Deutsche José Carreras Leukämie Stiftung (to S.K.), Bavarian Research Foundation (BAYCELLATOR to S.K.), the Bruno and Helene Jöster Foundation (360° CAR to S.K.), the Dr-Rurainski Foundation (to S.K.), the Monika Kutzner Foundation (to M.P.T. and S.K.) and an SNSF Postdoc.Mobility Fellowship (P500PB_214363 to M.P.T). G.K. and L.Z. are supported by the Ligue contre le Cancer (équipes labellisées); Institut National du Cancer (INCa); European Union Horizon 2020 research and innovation programmes Oncobiome (grant agreement number: 825410), Prevalung (grant agreement number 101095604), Agence Nationale de la Recherche under the France 2030 programme (reference number 21-ESRE-0028, ESR/Equipex + Onco-Pheno-Screen); Institut National du Cancer (INCa); Agence Nationale de la Recherche (ANR), that is, French Ministry of Health PIA5, ANR, program RHU5 ‘ANR-21-RHUS-0017′ IMMUNOLIFE and ANR-23-RHUS-0010 LUCA-pi; and Seerave Foundation. G.K. is supported by a European Research Council Advanced Investigator Award (ERC-2021-ADG, grant No. 101052444; project acronym: ICD-Cancer); SIRIC Cancer Research and Personalized Medicine (CARPEM, SIRIC CARPEM INCa-DGOS-Inserm-ITMO Cancer_18006 supported by Institut National du Cancer, Ministère des Solidarités et de la Santé and INSERM). This study contributes to the IdEx Université de Paris Cité ANR-18-IDEX-0001. L.Z. is supported by a European Research Council Advanced Investigator Award (ERC-2023-ADG, project acronym: MADCAM); a European Union Horizon 2020 T-OP Grant (Agreement No. 955575: Marie Curie training network for optimizing adoptive T cell therapy) and is part of the IHMCSA–European Microbiome Centers Consortium.
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S.K. has received honoraria from Cymab, Plectonic, TCR2 Inc., Miltenyi, Galapagos, Novartis, BMS and GSK. S.K. is an inventor of several patents in the field of immuno-oncology. S.K. received licence fees from TCR2 Inc. and Carina Biotech. S.K. received research support from TCR2 Inc., Tabby Therapeutics, Catalym GmBH, Plectonic GmBH and Arcus Bioscience for work unrelated to the article. G.K. has held research contracts with Daiichi Sankyo, Eleor, Kaleido, Lytix Pharma, PharmaMar, Osasuna Therapeutics, Samsara Therapeutics, Sanofi, Sutro, Tollys and Vascage. G.K. is on the Board of Directors of the Bristol Myers Squibb Foundation France. G.K. is a scientific co-founder of everImmune, Osasuna Therapeutics, Samsara Therapeutics and Therafast Bio. G.K. is on the scientific advisory boards of Hevolution, Institut Servier, Longevity Vision Funds and Rejuveron Life Sciences. G.K. is the inventor of patents covering therapeutic targeting of ageing, cancer, cystic fibrosis and metabolic disorders. L.Z. has held research contracts with GSK, Incyte, Lytix, Kaleido, Innovate Pharma, Daiichi Sankyo, Pilege, Merus, Transgene, 9m, Tusk and Roche, was on the on the Board of Directors of Transgene, is a co-founder of everImmune and holds patents covering the treatment of cancer and the therapeutic manipulation of the microbiota. G.K.’s brother, R. Kroemer, was an employee of Sanofi and now consults for Boehringer-Ingelheim. M.P.T. declares no competing interests.
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Trefny, M.P., Kroemer, G., Zitvogel, L. et al. Metabolites as agents and targets for cancer immunotherapy . Nat Rev Drug Discov 24, 764–784 (2025). https://doi.org/10.1038/s41573-025-01227-z
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DOI: https://doi.org/10.1038/s41573-025-01227-z
