Metabolites as signalling molecules in the tumour immune microenvironment

Metabolites as signalling molecules in the tumour immune microenvironment

  • Mao, Y. & Jiang, P. The crisscross between p53 and metabolism in cancer. Acta Biochim. Biophys. Sin. 55, 914–922 (2023).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

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

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Li, L. et al. p53 regulation of ammonia metabolism through urea cycle controls polyamine biosynthesis. Nature 567, 253–256 (2019). The article describes that increased urea cycle flux and polyamine biosynthesis caused by p53 loss are essential for tumor cell proliferation, with implications for p53 mutation-associated tissue pathologies.

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Mao, Y., Xia, Z., Xia, W. & Jiang, P. Metabolic reprogramming, sensing, and cancer therapy. Cell Rep. 43, 115064 (2024).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

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

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Liang, J. et al. Selective deficiency of mitochondrial respiratory complex I subunits Ndufs4/6 causes tumor immunogenicity. Nat. Cancer 6, 323–337 (2025).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Cheng, J., Xiao, Y. & Jiang, P. Fumarate integrates metabolism and immunity in diseases. Trends Endocrinol. Metab. https://doi.org/10.1016/j.tem.2025.03.008 (2025).

    Article 
    PubMed 

    Google Scholar
     

  • De Martino, M., Rathmell, J. C., Galluzzi, L. & Vanpouille-Box, C. Cancer cell metabolism and antitumour immunity. Nat. Rev. Immunol. 24, 654–669 (2024).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Cascone, T. et al. Increased tumor glycolysis characterizes immune resistance to adoptive T cell therapy. Cell Metab. 27, 977–987.e974 (2018).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Leone, R. D. et al. Glutamine blockade induces divergent metabolic programs to overcome tumor immune evasion. Science 366, 1013–1021 (2019). This study shows that the use of a glutamine antagonist, JHU083, can simultaneously shut down glycolysis and OXPHOS in mouse cancer cells while increasing OXPHOS in T cells, resulting in them adopting a long-lived, highly activated phenotype.

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Reina-Campos, M., Scharping, N. E. & Goldrath, A. W. CD8+ T cell metabolism in infection and cancer. Nat. Rev. Immunol. 21, 718–738 (2021).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Palm, W. & Thompson, C. B. Nutrient acquisition strategies of mammalian cells. Nature 546, 234–242 (2017).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

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

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Pucino, V., Bombardieri, M., Pitzalis, C. & Mauro, C. Lactate at the crossroads of metabolism, inflammation, and autoimmunity. Eur. J. Immunol. 47, 14–21 (2017).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Certo, M., Tsai, C. H., Pucino, V., Ho, P. C. & Mauro, C. Lactate modulation of immune responses in inflammatory versus tumour microenvironments. Nat. Rev. Immunol. 21, 151–161 (2021).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Zhang, W. et al. Lactate is a natural suppressor of RLR signaling by targeting MAVS. Cell 178, 176–189.e115 (2019).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Comito, G. et al. Lactate modulates CD4+ T-cell polarization and induces an immunosuppressive environment, which sustains prostate carcinoma progression via TLR8/miR21 axis. Oncogene 38, 3681–3695 (2019).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Lygerou, Z., Christophides, G. & Séraphin, B. A novel genetic screen for snRNP assembly factors in yeast identifies a conserved protein, Sad1p, also required for pre-mRNA splicing. Mol. Cell Biol. 19, 2008–2020 (1999).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Ding, R. et al. Lactate modulates RNA splicing to promote CTLA-4 expression in tumor-infiltrating regulatory T cells. Immunity 57, 528–540.e526 (2024).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Lu, S. X. et al. Pharmacologic modulation of RNA splicing enhances anti-tumor immunity. Cell 184, 4032–4047.e4031 (2021).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Kumagai, S. et al. Lactic acid promotes PD-1 expression in regulatory T cells in highly glycolytic tumor microenvironments. Cancer Cell 40, 201–218.e209 (2022).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Feng, Q. et al. Lactate increases stemness of CD8+ T cells to augment anti-tumor immunity. Nat. Commun. 13, 4981 (2022).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Wenes, M. et al. The mitochondrial pyruvate carrier regulates memory T cell differentiation and antitumor function. Cell Metab. 34, 731–746.e739 (2022).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Ranganathan, P. et al. GPR81, a cell-surface receptor for lactate, regulates intestinal homeostasis and protects mice from experimental colitis. J. Immunol. 200, 1781–1789 (2018).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Brown, T. P. et al. The lactate receptor GPR81 promotes breast cancer growth via a paracrine mechanism involving antigen-presenting cells in the tumor microenvironment. Oncogene 39, 3292–3304 (2020).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Roland, C. L. et al. Cell surface lactate receptor GPR81 is crucial for cancer cell survival. Cancer Res. 74, 5301–5310 (2014).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Wagner, W., Kania, K. D., Blauz, A. & Ciszewski, W. M. The lactate receptor (HCAR1/GPR81) contributes to doxorubicin chemoresistance via ABCB1 transporter up-regulation in human cervical cancer HeLa cells. J. Physiol. Pharmacol. 68, 555–564 (2017).

    PubMed 
    CAS 

    Google Scholar
     

  • Feng, J. et al. Tumor cell-derived lactate induces TAZ-dependent upregulation of PD-L1 through GPR81 in human lung cancer cells. Oncogene 36, 5829–5839 (2017).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Lundø, K. et al. Lactate receptor GPR81 drives breast cancer growth and invasiveness through regulation of ECM properties and Notch ligand DLL4. BMC Cancer 23, 1136 (2023).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Xing, W., Li, X., Zhou, Y., Li, M. & Zhu, M. Lactate metabolic pathway regulates tumor cell metastasis and its use as a new therapeutic target. Explor. med. 4, 542–560 (2023).


    Google Scholar
     

  • Baryla, M. et al. Oncometabolites-A link between cancer cells and tumor microenvironment. Biology 11, 270 (2022).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Mills, E. & O’Neill, L. A. Succinate: a metabolic signal in inflammation. Trends Cell Biol. 24, 313–320 (2014).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Zhang, Z. et al. Identification of lysine succinylation as a new post-translational modification. Nat. Chem. Biol. 7, 58–63 (2011).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Hirschey, M. D. & Zhao, Y. Metabolic regulation by lysine malonylation, succinylation, and glutarylation. Mol. Cell Proteom. 14, 2308–2315 (2015).

    Article 
    CAS 

    Google Scholar
     

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

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Wu, J. Y. et al. Cancer-derived succinate promotes macrophage polarization and cancer metastasis via succinate receptor. Mol. Cell 77, 213–227.e215 (2020).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Trauelsen, M. et al. Extracellular succinate hyperpolarizes M2 macrophages through SUCNR1/GPR91-mediated Gq signaling. Cell Rep. 35, 109246 (2021).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Xiao, Y. et al. Succinate is a natural suppressor of antiviral immune response by targeting MAVS. Front. Immunol. 13, 816378 (2022).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Gudgeon, N. et al. Succinate uptake by T cells suppresses their effector function via inhibition of mitochondrial glucose oxidation. Cell Rep. 40, 111193 (2022).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Rubic, T. et al. Triggering the succinate receptor GPR91 on dendritic cells enhances immunity. Nat. Immunol. 9, 1261–1269 (2008).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Tannahill, G. M. et al. Succinate is an inflammatory signal that induces IL-1beta through HIF-1alpha. Nature 496, 238–242 (2013). This study shows that LPS induces metabolic reprogramming in macrophages, resulting in a marked increase in succinate production, predominantly from glutamine, to stabilize HIF1-α, thereby impairing IFN-β production.

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Inamdar, S. et al. Succinate based polymers drive immunometabolism in dendritic cells to generate cancer immunotherapy. J. Control. Rel. 358, 541–554 (2023).

    Article 
    CAS 

    Google Scholar
     

  • Schmidt, C., Sciacovelli, M. & Frezza, C. Fumarate hydratase in cancer: a multifaceted tumour suppressor. Semin. Cell Dev. Biol. 98, 15–25 (2020).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Yamasaki, T. et al. Exploring a glycolytic inhibitor for the treatment of an FH-deficient type-2 papillary RCC. Nat. Rev. Urol. 8, 165–171 (2011).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Bevan, S. et al. Germline mutations in fumarate hydratase (FH) do not predispose to prostate cancer. Prostate Cancer Prostatic Dis. 6, 12–14 (2003).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Zecchini, V. et al. Fumarate induces vesicular release of mtDNA to drive innate immunity. Nature 615, 499–506 (2023).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Hooftman, A. et al. Macrophage fumarate hydratase restrains mtRNA-mediated interferon production. Nature 615, 490–498 (2023).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Xia, W., Mao, Y., Xia, Z., Cheng, J. & Jiang, P. Metabolic remodelling produces fumarate via the aspartate-argininosuccinate shunt in macrophages as an antiviral defence. Nat. Microbiol. 10, 1115–1129 (2025). Zecchini et al., Hooftman et al. and Xia et al. describe the roles of mitochondrial and cytosolic fumarate in enhancing innate immunity through mechanisms driven by the release of mitochondrial RNA and DNA, and MAVS succination, respectively, to activate interferon production and stimulate an inflammatory response.

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Xiao, M. et al. Inhibition of alpha-KG-dependent histone and DNA demethylases by fumarate and succinate that are accumulated in mutations of FH and SDH tumor suppressors. Genes. Dev. 26, 1326–1338 (2012).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Duan, Y. et al. ADSL-generated fumarate binds and inhibits STING to promote tumour immune evasion. Nat. Cell Biol. 27, 668–682 (2025).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Zhang, Z., Yang, Y., Chen, Y., Su, J. & Du, W. Malic enzyme 2 maintains metabolic state and anti-tumor immunity of CD8+ T cells. Mol. Cell 84, 3354–3370.e3357 (2024).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Gupta, V. K. et al. Hypoxia-driven oncometabolite L-2HG maintains stemness-differentiation balance and facilitates immune evasion in pancreatic cancer. Cancer Res. 81, 4001–4013 (2021).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Hvinden, I. C., Cadoux-Hudson, T., Schofield, C. J. & McCullagh, J. S. O. Metabolic adaptations in cancers expressing isocitrate dehydrogenase mutations. Cell Rep. Med. 2, 100469 (2021).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Xu, W. et al. Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of alpha-ketoglutarate-dependent dioxygenases. Cancer Cell 19, 17–30 (2011).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Wu, M. J. et al. Mutant IDH1 inhibition induces dsDNA sensing to activate tumor immunity. Science 385, eadl6173 (2024).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Zhao, M. et al. Malic enzyme 2 maintains protein stability of mutant p53 through 2-hydroxyglutarate. Nat. Metab. 4, 225–238 (2022).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Friedrich, M. et al. Tryptophan metabolism drives dynamic immunosuppressive myeloid states in IDH-mutant gliomas. Nat. Cancer 2, 723–740 (2021).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Feng, S. et al. Blockage of L2HGDH-mediated S-2HG catabolism orchestrates macrophage polarization to elicit antitumor immunity. Cell Rep. 43, 114300 (2024).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Bunse, L. et al. Suppression of antitumor T cell immunity by the oncometabolite (R)-2-hydroxyglutarate. Nat. Med. 24, 1192–1203 (2018).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Tyrakis, P. A. et al. S-2-hydroxyglutarate regulates CD8+ T-lymphocyte fate. Nature 540, 236–241 (2016).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Foskolou, I. P., Bunse, L. & Van den Bossche, J. 2-hydroxyglutarate rides the cancer-immunity cycle. Curr. Opin. Biotechnol. 83, 102976 (2023).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Peace, C. G. & O’Neill, L. A. The role of itaconate in host defense and inflammation. J. Clin. Invest. 132, e148548 (2022).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

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

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Lin, H. et al. Itaconate transporter SLC13A3 impairs tumor immunity via endowing ferroptosis resistance. Cancer Cell 42, 2032–2044.e2036 (2024).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Zhao, Y. et al. Neutrophils resist ferroptosis and promote breast cancer metastasis through aconitate decarboxylase 1. Cell Metab. 35, 1688–1703.e1610 (2023).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Kelly, B. & Pearce, E. L. Amino assets: how amino acids support immunity. Cell Metab. 32, 154–175 (2020).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Recouvreux, M. V. et al. Glutamine mimicry suppresses tumor progression through asparagine metabolism in pancreatic ductal adenocarcinoma. Nat. Cancer 5, 100–113 (2024).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Reinfeld, B. I. et al. Cell-programmed nutrient partitioning in the tumour microenvironment. Nature 593, 282–288 (2021). This study shows that in the TME, myeloid cells have the greatest capacity to take up intratumoral glucose, followed by T cells and cancer cells, and cancer cells have the greatest uptake of glutamine; it describes how this distinct nutrient partitioning occurs.

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Nakaya, M. et al. Inflammatory T cell responses rely on amino acid transporter ASCT2 facilitation of glutamine uptake and mTORC1 kinase activation. Immunity 40, 692–705 (2014).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Wei, W. et al. Asparagine drives immune evasion in bladder cancer via RIG-I stability and type I IFN signaling. J. Clin. Invest. 135, e186648 (2025).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Wu, J. et al. Asparagine enhances LCK signalling to potentiate CD8+ T-cell activation and anti-tumour responses. Nat. Cell Biol. 23, 75–86 (2021).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Gnanaprakasam, J. N. R. et al. Asparagine restriction enhances CD8+ T cell metabolic fitness and antitumoral functionality through an NRF2-dependent stress response. Nat. Metab. 5, 1423–1439 (2023).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Chang, H. C. et al. Asparagine deprivation enhances T cell antitumour response in patients via ROS-mediated metabolic and signal adaptations. Nat. Metab. 7, 918–927 (2025).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Ala, M. The footprint of kynurenine pathway in every cancer: a new target for chemotherapy. Eur. J. Pharmacol. 896, 173921 (2021).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Cheong, J. E. & Sun, L. Targeting the IDO1/TDO2-KYN-AhR pathway for cancer immunotherapy – challenges and opportunities. Trends Pharmacol. Sci. 39, 307–325 (2018).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Campesato, L. F. et al. Blockade of the AHR restricts a Treg-macrophage suppressive axis induced by L-kynurenine. Nat. Commun. 11, 4011 (2020).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Takenaka, M. C. et al. Control of tumor-associated macrophages and T cells in glioblastoma via AHR and CD39. Nat. Neurosci. 22, 729–740 (2019).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Chen, E. et al. FLI1 promotes IFN-gamma-induced kynurenine production to impair anti-tumor immunity. Nat. Commun. 15, 4590 (2024).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Liu, Y. et al. Tumor-repopulating cells induce PD-1 expression in CD8+ T cells by transferring kynurenine and AhR activation. Cancer Cell 33, 480–494.e487 (2018).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Boadle-Biber, M. C. Regulation of serotonin synthesis. Prog. Biophys. Mol. Biol. 60, 1–15 (1993).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Goralczyk-Binkowska, A., Szmajda-Krygier, D. & Kozlowska, E. The microbiota–gut–brain axis in psychiatric disorders. Int. J. Mol. Sci. 23, 11245 (2022).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Balakrishna, P., George, S., Hatoum, H. & Mukherjee, S. Serotonin pathway in cancer. Int. J. Mol. Sci. 22, 1268 (2021).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Dizeyi, N. et al. Serotonin activates MAP kinase and PI3K/Akt signaling pathways in prostate cancer cell lines. Urol. Oncol-Semin Ori 29, 436–445 (2011).

    Article 
    CAS 

    Google Scholar
     

  • Jiang, S.-H. et al. Increased serotonin signaling contributes to the warburg effect in pancreatic tumor cells under metabolic stress and promotes growth of pancreatic tumors in mice. Gastroenterology 153, 277–291.e219 (2017).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Sola-Penna, M. et al. Serotonin activates glycolysis and mitochondria biogenesis in human breast cancer cells through activation of the Jak1/STAT3/ERK1/2 and adenylate cyclase/PKA, respectively. Brit J. Cancer 122, 194–208 (2020).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • De las Casas-Engel, M. et al. Serotonin skews human macrophage polarization through HTR2B and HTR7. J. Immunol. 190, 2301–2310 (2013).

    Article 

    Google Scholar
     

  • Cheng, H. H. et al. Control of cyclooxygenase-2 expression and tumorigenesis by endogenous 5-methoxytryptophan. Proc. Natl Acad. Sci. USA 109, 13231–13236 (2012).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Al-Habsi, M. et al. Spermidine activates mitochondrial trifunctional protein and improves antitumor immunity in mice. Science 378, eabj3510 (2022).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Hibino, S. et al. Tumor cell-derived spermidine is an oncometabolite that suppresses TCR clustering for intratumoral CD8+ T cell activation. Proc. Natl Acad. Sci. USA 120, e2305245120 (2023).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Zhu, Y. et al. Cancer cell-derived arginine fuels polyamine biosynthesis in tumor-associated macrophages to promote immune evasion. Cancer Cell 43, 1045–1060.e1047 (2025).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Holbert, C. E., Cullen, M. T., Casero, R. A. Jr. & Stewart, T. M. Polyamines in cancer: integrating organismal metabolism and antitumour immunity. Nat. Rev. Cancer 22, 467–480 (2022).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Murray, P. J., Rathmell, J. & Pearce, E. Snapshot: immunometabolism. Cell Metab. 22, 190–190.e191 (2015).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Salimian Rizi, B. et al. Nitric oxide mediates metabolic coupling of omentum-derived adipose stroma to ovarian and endometrial cancer cells. Cancer Res. 75, 456–471 (2015).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Mao, Y., Shi, D., Li, G. & Jiang, P. Citrulline depletion by ASS1 is required for proinflammatory macrophage activation and immune responses. Mol. Cell 82, 527–541.e527 (2022).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Cane, S., Geiger, R. & Bronte, V. The roles of arginases and arginine in immunity. Nat. Rev. Immunol. 25, 266–284 (2024).

    Article 
    PubMed 

    Google Scholar
     

  • Cui, H. et al. Arg-tRNA synthetase links inflammatory metabolism to RNA splicing and nuclear trafficking via SRRM2. Nat. Cell Biol. 25, 592–603 (2023). This article shows that arginine depletion during inflammation decreases levels of nuclear-localized arginyl-tRNA synthetase (ArgRS) and describes how arginine or ArgRS depletion alters cellular metabolism and peptide–MHC-I presentation.

    Article 
    PubMed 
    CAS 

    Google Scholar
     

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

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Chantranupong, L. et al. The CASTOR proteins are arginine sensors for the mTORC1 pathway. Cell 165, 153–164 (2016).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Soula, M. et al. Glycosphingolipid synthesis mediates immune evasion in KRAS-driven cancer. Nature 633, 451–458 (2024).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Kloosterman, D. J. et al. Macrophage-mediated myelin recycling fuels brain cancer malignancy. Cell 187, 5336–5356.e5330 (2024).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Fan, H. et al. Trans-vaccenic acid reprograms CD8+ T cells and anti-tumour immunity. Nature 623, 1034–1043 (2023).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Nava Lauson, C. B. et al. Linoleic acid potentiates CD8+ T cell metabolic fitness and antitumor immunity. Cell Metab. 35, 633–650.e639 (2023).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Lacher, S. B. et al. PGE2 limits effector expansion of tumour-infiltrating stem-like CD8+ T cells. Nature 629, 417–425 (2024).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Yu, L. et al. Tumor-derived arachidonic acid reprograms neutrophils to promote immune suppression and therapy resistance in triple-negative breast cancer. Immunity 58, 909–925.e907 (2025).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Ping, Y. et al. PD-1 signaling limits expression of phospholipid phosphatase 1 and promotes intratumoral CD8+ T cell ferroptosis. Immunity 57, 2122–2139.e2129 (2024).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Belabed, M. et al. Cholesterol mobilization regulates dendritic cell maturation and the immunogenic response to cancer. Nat. Immunol. 26, 188–199 (2025).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Mukhopadhya, I. & Louis, P. Gut microbiota-derived short-chain fatty acids and their role in human health and disease. Nat. Rev. Microbiol. 23, 635–651 (2025).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Matsushita, M. et al. Gut microbiota-derived short-chain fatty acids promote prostate cancer growth via IGF1 signaling. Cancer Res. 81, 4014–4026 (2021).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Mathewson, N. D. et al. Gut microbiome–derived metabolites modulate intestinal epithelial cell damage and mitigate graft-versus-host disease. Nat. Immunol. 17, 505–513 (2016).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Hu, C. et al. Gut microbiota-derived short-chain fatty acids regulate group 3 innate lymphoid cells in HCC. Hepatology 77, 48–64 (2023).

    Article 
    PubMed 

    Google Scholar
     

  • Luu, M. et al. Microbial short-chain fatty acids modulate CD8+ T cell responses and improve adoptive immunotherapy for cancer. Nat. Commun. 12, 4077 (2021).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Bachem, A. et al. Microbiota-derived short-chain fatty acids promote the memory potential of antigen-activated CD8+ T cells. Immunity 51, 285–297.e285 (2019).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Zhang, D. et al. Metabolic regulation of gene expression by histone lactylation. Nature 574, 575–580 (2019). This article defines lactate-derived lactylation of histone lysine residues, a phenomenon that can epigenetically modify gene transcription.

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Yu, J. et al. Histone lactylation drives oncogenesis by facilitating m6A reader protein YTHDF2 expression in ocular melanoma. Genome Biol. 22, 85 (2021).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Chen, Y. et al. Metabolic regulation of homologous recombination repair by MRE11 lactylation. Cell 187, 294–311.e221 (2024).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Zong, Z. et al. Alanyl-tRNA synthetase, AARS1, is a lactate sensor and lactyltransferase that lactylates p53 and contributes to tumorigenesis. Cell 187, 2375–2392.e2333 (2024).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • De Leo, A. et al. Glucose-driven histone lactylation promotes the immunosuppressive activity of monocyte-derived macrophages in glioblastoma. Immunity 57, 1105–1123.e1108 (2024).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Xiong, J. et al. Lactylation-driven METTL3-mediated RNA m(6)A modification promotes immunosuppression of tumor-infiltrating myeloid cells. Mol. Cell 82, 1660–1677.e1610 (2022).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Li, H., Sun, L., Gao, P. & Hu, H. Lactylation in cancer: current understanding and challenges. Cancer Cell 42, 1803–1807 (2024).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Bardella, C. et al. Aberrant succination of proteins in fumarate hydratase-deficient mice and HLRCC patients is a robust biomarker of mutation status. J. Pathol. 225, 4–11 (2011).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Blatnik, M., Frizzell, N., Thorpe, S. R. & Baynes, J. W. Inactivation of glyceraldehyde-3-phosphate dehydrogenase by fumarate in diabetes: formation of S-(2-succinyl)cysteine, a novel chemical modification of protein and possible biomarker of mitochondrial stress. Diabetes 57, 41–49 (2008).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Zheng, L. et al. Fumarate induces redox-dependent senescence by modifying glutathione metabolism. Nat. Commun. 6, 6001 (2015).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Kinch, L., Grishin, N. V. & Brugarolas, J. Succination of Keap1 and activation of Nrf2-dependent antioxidant pathways in FH-deficient papillary renal cell carcinoma type 2. Cancer Cell 20, 418–420 (2011).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Kornberg, M. D. et al. Dimethyl fumarate targets GAPDH and aerobic glycolysis to modulate immunity. Science 360, 449–453 (2018).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Mills, E. L. et al. Itaconate is an anti-inflammatory metabolite that activates Nrf2 via alkylation of KEAP1. Nature 556, 113–117 (2018). This study describes a role for itaconate, production of which can be induced by type I interferons, in alkylating KEAP1 to increase the expression of antioxidant and anti-inflammatory genes upon lipopolysaccharide stimulation in macrophages.

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Liao, S. T. et al. 4-Octyl itaconate inhibits aerobic glycolysis by targeting GAPDH to exert anti-inflammatory effects. Nat. Commun. 10, 5091 (2019).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Qin, W. et al. S-glycosylation-based cysteine profiling reveals regulation of glycolysis by itaconate. Nat. Chem. Biol. 15, 983–991 (2019).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • 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.e910 (2023). This study describes a role for tumour cell-derived fumarate accumulation caused by fumarate hydratase deficiency in inhibiting TCR signalling by succinating ZAP70 in tumour-infiltrating CD8+ T cells as a metabolic barrier to CD8+ T cell anti-tumour function.

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Sreedhar, A., Wiese, E. K. & Hitosugi, T. Enzymatic and metabolic regulation of lysine succinylation. Genes. Dis. 7, 166–171 (2020).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Li, L. et al. SIRT7 is a histone desuccinylase that functionally links to chromatin compaction and genome stability. Nat. Commun. 7, 12235 (2016).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Wang, Y. et al. KAT2A coupled with the α-KGDH complex acts as a histone H3 succinyltransferase. Nature 552, 273–277 (2017).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Kurmi, K. et al. Carnitine palmitoyltransferase 1A has a lysine succinyltransferase activity. Cell Rep. 22, 1365–1373 (2018).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Abril, Y. L. N. et al. Pharmacological and genetic perturbation establish SIRT5 as a promising target in breast cancer. Oncogene 40, 1644–1658 (2021).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Park, J. et al. SIRT5-mediated lysine desuccinylation impacts diverse metabolic pathways. Mol. Cell 50, 919–930 (2013).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Wang, F. et al. SIRT5 desuccinylates and activates pyruvate kinase M2 to block macrophage IL-1β production and to prevent DSS-induced colitis in mice. Cell Rep. 19, 2331–2344 (2017).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Jiang, S. & Yan, W. Succinate in the cancer–immune cycle. Cancer Lett. 390, 45–47 (2017).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Casero, R. A. Jr., Murray Stewart, T. & Pegg, A. E. Polyamine metabolism and cancer: treatments, challenges and opportunities. Nat. Rev. Cancer 18, 681–695 (2018).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Zhou, J. et al. Spermidine-mediated hypusination of translation factor EIF5A improves mitochondrial fatty acid oxidation and prevents non-alcoholic steatohepatitis progression. Nat. Commun. 13, 5202 (2022).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Coni, S. et al. Blockade of EIF5A hypusination limits colorectal cancer growth by inhibiting MYC elongation. Cell Death Dis. 11, 1045 (2020).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Liao, R. et al. AMD1 promotes breast cancer aggressiveness via a spermidine-eIF5A hypusination-TCF4 axis. Breast Cancer Res. 26, 70 (2024).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Puleston, D. J. et al. Polyamine metabolism is a central determinant of helper T cell lineage fidelity. Cell 184, 4186–4202.e4120 (2021).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Puleston, D. J. et al. Polyamines and eIF5A hypusination modulate mitochondrial respiration and macrophage activation. Cell Metab. 30, 352–363.e358 (2019).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Zeng, J. et al. Targeted inhibition of eIF5A(hpu) suppresses tumor growth and polarization of M2-like tumor-associated macrophages in oral cancer. Cell Death Dis. 14, 579 (2023).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Rogowski, K. et al. A family of protein-deglutamylating enzymes associated with neurodegeneration. Cell 143, 564–578 (2010).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Garnham, C. P. et al. Multivalent microtubule recognition by tubulin tyrosine ligase-like family glutamylases. Cell 161, 1112–1123 (2015).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Valenstein, M. L. & Roll-Mecak, A. Graded control of microtubule severing by tubulin glutamylation. Cell 164, 911–921 (2016).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Torrino, S. et al. Mechano-induced cell metabolism promotes microtubule glutamylation to force metastasis. Cell Metab. 33, 1342–1357.e1310 (2021).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Chen, X. et al. The moonlighting function of glutamin synthase 2 promotes immune evasion of pancreatic ductal adenocarcinoma by tubulin tyrosine ligase-like 1-mediated yes1 associated transcriptional regulator glutamylation. Gastroenterology 168, 1137–1152 (2025).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Xia, P. et al. Glutamylation of the DNA sensor cGAS regulates its binding and synthase activity in antiviral immunity. Nat. Immunol. 17, 369–378 (2016).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Liu, B. et al. IL-7Ralpha glutamylation and activation of transcription factor Sall3 promote group 3 ILC development. Nat. Commun. 8, 231 (2017).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Verdin, E. & Ott, M. 50 years of protein acetylation: from gene regulation to epigenetics, metabolism and beyond. Nat. Rev. Mol. Cell Biol. 16, 258–264 (2015).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Bhaumik, S. R., Smith, E. & Shilatifard, A. Covalent modifications of histones during development and disease pathogenesis. Nat. Struct. Mol. Biol. 14, 1008–1016 (2007).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Gu, W. & Roeder, R. G. Activation of p53 sequence-specific DNA binding by acetylation of the p53 C-terminal domain. Cell 90, 595–606 (1997).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Guertin, D. A. & Wellen, K. E. Acetyl-CoA metabolism in cancer. Nat. Rev. Cancer 23, 156–172 (2023).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Chowdhury, S. et al. Intracellular acetyl CoA potentiates the therapeutic efficacy of antitumor CD8+ T cells. Cancer Res. 82, 2640–2655 (2022).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Qiu, J. et al. Acetate promotes T cell effector function during glucose restriction. Cell Rep. 27, 2063–2074.e2065 (2019).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Noe, J. T. et al. Lactate supports a metabolic-epigenetic link in macrophage polarization. Sci. Adv. 7, eabi8602 (2021).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Michishita, E. et al. SIRT6 is a histone H3 lysine 9 deacetylase that modulates telomeric chromatin. Nature 452, 492–496 (2008).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Kingston, R. E. & Narlikar, G. J. ATP-dependent remodeling and acetylation as regulators of chromatin fluidity. Gene Dev. 13, 2339–2352 (1999).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Zou, W. & Green, D. R. Beggars banquet: metabolism in the tumor immune microenvironment and cancer therapy. Cell Metab. 35, 1101–1113 (2023).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Fang, L. et al. Methionine restriction promotes cGAS activation and chromatin untethering through demethylation to enhance antitumor immunity. Cancer Cell 41, 1118–1133.e1112 (2023).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Roy, D. G. et al. Methionine metabolism shapes T helper cell responses through regulation of epigenetic reprogramming. Cell Metab. 31, 250–266.e259 (2020).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Sinclair, L. V. et al. Antigen receptor control of methionine metabolism in T cells. Elife 8, e44210 (2019).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Pandit, M. et al. Methionine consumption by cancer cells drives a progressive upregulation of PD-1 expression in CD4 T cells. Nat. Commun. 14, 2593 (2023).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

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

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Rais, R. et al. Discovery of DRP-104, a tumor-targeted metabolic inhibitor prodrug. Sci. Adv. 8, eabq5925 (2022).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Dikshit, A. et al. Potential utility of synthetic D-lactate polymers in skin cancer. JID Innov. 1, 100043 (2021).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 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 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Goldberg, F. W. et al. Discovery of clinical candidate AZD0095, a selective inhibitor of monocarboxylate transporter 4 (MCT4) for oncology. J. Med. Chem. 66, 384–397 (2023).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Dhillon, S. Ivosidenib: first global approval. Drugs 78, 1509–1516 (2018).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Stein, E. M. Enasidenib, a targeted inhibitor of mutant IDH2 proteins for treatment of relapsed or refractory acute myeloid leukemia. Future Oncol. 14, 23–40 (2018).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • DiNardo, C. D. et al. Glutaminase inhibition in combination with azacytidine in myelodysplastic syndromes: a phase 1b/2 clinical trial and correlative analyses. Nat. Cancer 5, 1515–1533 (2024).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Soth, M. J. et al. Discovery of IPN60090, a clinical stage selective glutaminase-1 (GLS-1) inhibitor with excellent pharmacokinetic and physicochemical properties. J. Med. Chem. 63, 12957–12977 (2020).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Vanauberg, D., Schulz, C. & Lefebvre, T. Involvement of the pro-oncogenic enzyme fatty acid synthase in the hallmarks of cancer: a promising target in anti-cancer therapies. Oncogenesis 12, 16 (2023).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • 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 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Cicin, I. et al. Epacadostat plus pembrolizumab versus placebo plus pembrolizumab for advanced urothelial carcinoma: results from the randomized phase III ECHO-303/KEYNOTE-698 study. BMC Cancer 23, 1256 (2024).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Steggerda, S. M. et al. Inhibition of arginase by CB-1158 blocks myeloid cell-mediated immune suppression in the tumor microenvironment. J. Immunother. Cancer 5, 101 (2017).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Ward, P. S. & Thompson, C. B. Metabolic reprogramming: a cancer hallmark even warburg did not anticipate. Cancer Cell 21, 297–308 (2012).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

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

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Chang, C. H. et al. Metabolic competition in the tumor microenvironment is a driver of cancer progression. Cell 162, 1229–1241 (2015). This article shows that there is competition for glucose between tumour cells and T cells in the TME and describes how glucose consumption by tumours restricts T cells.

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Altman, B. J., Stine, Z. E. & Dang, C. V. From Krebs to clinic: glutamine metabolism to cancer therapy. Nat. Rev. Cancer 16, 749 (2016).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Koundouros, N. & Poulogiannis, G. Reprogramming of fatty acid metabolism in cancer. Br. J. Cancer 122, 4–22 (2020).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Schiliro, C. & Firestein, B. L. Mechanisms of metabolic reprogramming in cancer cell supporting enhanced growth proliferation. Cell 10, 1056 (2021).

    Article 
    CAS 

    Google Scholar
     

  • Gubser, P. M. et al. Rapid effector function of memory CD8+ T cells requires an immediate-early glycolytic switch. Nat. Immunol. 14, 1064–1072 (2013).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Pearce, E. L. & Pearce, E. J. Metabolic pathways in immune cell activation and quiescence. Immunity 38, 633–643 (2013).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Van der Windt, G. J. et al. Mitochondrial respiratory capacity is a critical regulator of CD8+ T cell memory development. Immunity 36, 68–78 (2012).

    Article 
    PubMed 

    Google Scholar
     

  • Michalek, R. D. et al. Cutting edge: distinct glycolytic and lipid oxidative metabolic programs are essential for effector and regulatory CD4+ T cell subsets. J. Immunol. 186, 3299–3303 (2011).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Berod, L. et al. De novo fatty acid synthesis controls the fate between regulatory T and T helper 17 cells. Nat. Med. 20, 1327–1333 (2014).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Ikeda, H. et al. Immune evasion through mitochondrial transfer in the tumour microenvironment. Nature 638, 225–236 (2025).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Waters, L. R., Ahsan, F. M., Wolf, D. M., Shirihai, O. & Teitell, M. A. Initial B cell activation induces metabolic reprogramming and mitochondrial remodeling. iScience 5, 99–109 (2018).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Cheng, J. et al. Fumarate suppresses B-cell activation and function through direct inactivation of LYN. Nat. Chem. Biol. 18, 954–962 (2022).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Zhang, B. et al. B cell-derived GABA elicits IL-10+ macrophages to limit anti-tumour immunity. Nature 599, 471–476 (2021).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Rodríguez-Prados, J.-C. et al. Substrate fate in activated macrophages: a comparison between innate, classic, and alternative activation. J. Immunol. 185, 605–614 (2010).

    Article 
    PubMed 

    Google Scholar
     

  • Jha, A. K. et al. Network integration of parallel metabolic and transcriptional data reveals metabolic modules that regulate macrophage polarization. Immunity 42, 419–430 (2015).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Kumar, S. & Dikshit, M. Metabolic insight of neutrophils in health and disease. Front. Immunol. 10, 2099 (2019).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Azevedo, E. P. et al. A metabolic shift toward pentose phosphate pathway is necessary for amyloid fibril-and phorbol 12-myristate 13-acetate-induced neutrophil extracellular trap (NET) formation. J. Biol. Chem. 290, 22174–22183 (2015).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Grant, G. & Ferrer, C. M. The role of the immune tumor microenvironment in shaping metastatic dissemination, dormancy, and outgrowth. Trends Cell Biol. https://doi.org/10.1016/j.tcb.2025.05.006 (2025).

    Article 
    PubMed 

    Google Scholar