DGAT1 mediates sex-specific CD8+ T cell antitumour responses.
| Title: | DGAT1 mediates sex-specific CD8+ T cell antitumour responses. |
|---|---|
| Authors: | Madi A; Division of T Cell Metabolism, German Cancer Research Center (DKFZ), Heidelberg, Germany. a.madi@dkfz-heidelberg.de.; Division of Immune Diversity, German Cancer Research Center (DKFZ), Heidelberg, Germany. a.madi@dkfz-heidelberg.de.; Department of Experimental Immunology, Institute of Immunology, University of Tübingen, Tübingen, Germany. a.madi@dkfz-heidelberg.de.; M3 Research Center, University Hospital Tübingen, University of Tübingen, Tübingen, Germany. a.madi@dkfz-heidelberg.de.; Shi H; State Key Laboratory of Immune Response and Immunotherapy, Institute of Health and Medicine, Hefei Comprehensive National Science Center, Hefei, China.; School of Basic Medical Sciences, Anhui Provincial Key Laboratory of Environment and Population Health Across the Life Course, Center for Big Data and Population Health of IHM, Anhui Medical University, Hefei, China.; Su M; State Key Laboratory of Reproductive Medicine and Offspring Health, Nanjing Medical University, Nanjing, China.; Mady A; Data Engineering and Analytics Master program, Technical University of Munich (TUM), Garching, Germany.; Lv B; State Key Laboratory of Immune Response and Immunotherapy, School of Basic Medical Sciences, Division of life Sciences and Medicine, University of Science and Technology of China, Hefei, China.; Wang H; State Key Laboratory of Immune Response and Immunotherapy, Institute of Health and Medicine, Hefei Comprehensive National Science Center, Hefei, China.; Yang B; State Key Laboratory of Immune Response and Immunotherapy, Institute of Health and Medicine, Hefei Comprehensive National Science Center, Hefei, China.; Yan Z; State Key Laboratory of Immune Response and Immunotherapy, Institute of Health and Medicine, Hefei Comprehensive National Science Center, Hefei, China.; Jin X; State Key Laboratory of Immune Response and Immunotherapy, Institute of Health and Medicine, Hefei Comprehensive National Science Center, Hefei, China.; Wu L; State Key Laboratory of Immune Response and Immunotherapy, Institute of Health and Medicine, Hefei Comprehensive National Science Center, Hefei, China.; Lv M; State Key Laboratory of Immune Response and Immunotherapy, Institute of Health and Medicine, Hefei Comprehensive National Science Center, Hefei, China.; Hering M; Division of T Cell Metabolism, German Cancer Research Center (DKFZ), Heidelberg, Germany.; Ma S; State Key Laboratory of Immune Response and Immunotherapy, Institute of Health and Medicine, Hefei Comprehensive National Science Center, Hefei, China.; Mieg A; Division of T Cell Metabolism, German Cancer Research Center (DKFZ), Heidelberg, Germany.; Zettl F; Division of T Cell Metabolism, German Cancer Research Center (DKFZ), Heidelberg, Germany.; Yan X; Division of T Cell Metabolism, German Cancer Research Center (DKFZ), Heidelberg, Germany.; Division of Immune Diversity, German Cancer Research Center (DKFZ), Heidelberg, Germany.; Mohr K; Division of T Cell Metabolism, German Cancer Research Center (DKFZ), Heidelberg, Germany.; Knabe N; Division of T Cell Metabolism, German Cancer Research Center (DKFZ), Heidelberg, Germany.; Poschet G; Metabolomics Core Technology Platform, Centre for Organismal Studies (COS), Heidelberg University, Heidelberg, Germany.; Richter K; Electron Microscopy core facility, German Cancer Research Center (DKFZ), Heidelberg, Germany.; Schleußner N; Division of Cancer Progression and Metastasis, German Cancer Research Center (DKFZ), Heidelberg, Germany.; Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Heidelberg, Germany.; Department of General, Visceral and Transplantation Surgery, University Hospital Heidelberg, University Heidelberg, Heidelberg, Germany.; Department of General, Visceral, Thorax and Transplant Surgery, University Hospital of Cologne, Cologne, Germany.; Jackstadt RF; Division of Cancer Progression and Metastasis, German Cancer Research Center (DKFZ), Heidelberg, Germany.; Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Heidelberg, Germany.; Loges S; Division of Personalized Medical Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.; Papavasiliou FN; Division of Immune Diversity, German Cancer Research Center (DKFZ), Heidelberg, Germany.; Wang X; State Key Laboratory of Reproductive Medicine and Offspring Health, Nanjing Medical University, Nanjing, China. xiwang@njmu.edu.cn.; Wu J; State Key Laboratory of Immune Response and Immunotherapy, Institute of Health and Medicine, Hefei Comprehensive National Science Center, Hefei, China. jingxia.wu@ihm.ac.cn.; School of Basic Medical Sciences, Anhui Provincial Key Laboratory of Environment and Population Health Across the Life Course, Center for Big Data and Population Health of IHM, Anhui Medical University, Hefei, China. jingxia.wu@ihm.ac.cn.; Cui G; Division of T Cell Metabolism, German Cancer Research Center (DKFZ), Heidelberg, Germany. gcui@ustc.edu.cn.; State Key Laboratory of Immune Response and Immunotherapy, Institute of Health and Medicine, Hefei Comprehensive National Science Center, Hefei, China. gcui@ustc.edu.cn.; State Key Laboratory of Immune Response and Immunotherapy, School of Basic Medical Sciences, Division of life Sciences and Medicine, University of Science and Technology of China, Hefei, China. gcui@ustc.edu.cn. |
| Source: | Nature metabolism [Nat Metab] 2026 Mar; Vol. 8 (3), pp. 685-703. Date of Electronic Publication: 2026 Mar 20. |
| Publication Type: | Journal Article |
| Language: | English |
| Journal Info: | Publisher: Springer Nature Country of Publication: Germany NLM ID: 101736592 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2522-5812 (Electronic) Linking ISSN: 25225812 NLM ISO Abbreviation: Nat Metab Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: Berlin : Springer Nature, [2019]- |
| MeSH Terms: | Diacylglycerol O-Acyltransferase*/metabolism ; Diacylglycerol O-Acyltransferase*/genetics ; CD8-Positive T-Lymphocytes*/immunology ; CD8-Positive T-Lymphocytes*/metabolism; Receptors, Androgen/metabolism ; Fatty Acids/metabolism ; Animals ; Female ; Male ; Mice ; Endoplasmic Reticulum Stress ; Signal Transduction ; Mice, Inbred C57BL ; Sex Characteristics ; Mice, Knockout |
| Abstract: | Fatty acid (FA) oxidation plays an important role in T cell responses. However, whether DGAT1-mediated FA esterification to triacylglycerol also regulates T cell function remains unclear. Here we uncover a sexually dimorphic requirement for DGAT1 expression in CD8+ tumour-infiltrating lymphocyte function. In female mice, T cell-specific Dgat1 deficiency improves mitochondrial metabolic fitness and expands the pool of progenitor exhausted CD8+ T (Tex) cells to sustain antitumour responses. In male mice, however, Dgat1 deficiency leads to FA peroxidation, endoplasmic reticulum (ER) stress and CD8+ Tex cell death. We show that these effects are mediated by androgen receptor (AR) signalling. Deletion of Ar, overexpression of glutathione peroxidase 4, or inhibition of ER stress-induced cell death rescues Dgat1-deficient CD8+ T cell survival and promotes antitumour responses in male mice. Overall, this study suggests that DGAT1 detoxifies AR signalling in male mice to protect against ER stress-induced cell death and maintain T cell stemness, and uncovers sex-specific metabolic adaptations in the tumour microenvironment.; (© 2026. The Author(s), under exclusive licence to Springer Nature Limited.) |
| Competing Interests: | Competing interests: A patent application has been filed by A. Madi and G.C. based on the data described in this study. G.C. receives research funding from Bayer AG and Boehringer Ingelheim. The funding has no direct relevance to the findings presented in this study. The other authors declare no competing interests. |
| References: | McLane, L. M., Abdel-Hakeem, M. S. & Wherry, E. J. CD8 T cell exhaustion during chronic viral infection and cancer. Annu. Rev. Immunol. 37, 457–495 (2019).; Binnewies, M. et al. Understanding the tumor immune microenvironment (TIME) for effective therapy. Nat. Med. 24, 541–550 (2018). (PMID: 10.1038/s41591-018-0014-x296864255998822); 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 (2021).; 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).; Im, S. J. et al. Defining CD8+ T cells that provide the proliferative burst after PD-1 therapy. Nature 537, 417–421 (2016).; Siddiqui, I. et al. Intratumoral Tcf1+PD-1+CD8+ T cells with stem-like properties promote tumor control in response to vaccination and checkpoint blockade immunotherapy. Immunity 50, 195–211 (2019).; Sade-Feldman, M. et al. Defining T cell states associated with response to checkpoint immunotherapy in melanoma. Cell 175, 998–1013.e20 (2018).; Zander, R. et al. CD4+ T cell help is required for the formation of a cytolytic CD8+ T cell subset that protects against chronic infection and cancer. Immunity 51, 1028–1042 (2019).; Hudson, W. H. et al. Proliferating transitory T cells with an effector-like transcriptional signature emerge from PD-1+ stem-like CD8+ T cells during chronic infection. Immunity 51, 1043–1058 (2019).; Im, S. J., Konieczny, B. T., Hudson, W. H., Masopust, D. & Ahmed, R. PD-1+ stemlike CD8 T cells are resident in lymphoid tissues during persistent LCMV infection. Proc. Natl Acad. Sci. USA 117, 4292–4299 (2020).; Pauken, K. E. et al. Epigenetic stability of exhausted T cells limits durability of reinvigoration by PD-1 blockade. Science 354, 1160–1165 (2016). (PMID: 10.1126/science.aaf2807277897955484795); Sen, D. R. et al. The epigenetic landscape of T cell exhaustion. Science 354, 1165–1169 (2016). (PMID: 10.1126/science.aae0491277897995497589); Chung, H. K., McDonald, B. & Kaech, S. M. The architectural design of CD8+ T cell responses in acute and chronic infection: Parallel structures with divergent fates. J. Exp. Med. 218, e20201730 (2021).; Zehn, D., Thimme, R., Lugli, E., de Almeida, G. P. & Oxenius, A. ‘Stem-like’ precursors are the fount to sustain persistent CD8+ T cell responses. Nat. Immunol. 23, 836–847 (2022).; Pearce, E. L. et al. Enhancing CD8 T-cell memory by modulating fatty acid metabolism. Nature 460, 103–107 (2009). (PMID: 10.1038/nature08097194948122803086); Wu, H. et al. Mitochondrial dysfunction promotes the transition of precursor to terminally exhausted T cells through HIF-1α-mediated glycolytic reprogramming. Nat. Commun. 14, 6858 (2023). (PMID: 10.1038/s41467-023-42634-33789123010611730); Cui, G. et al. IL-7-induced glycerol transport and TAG synthesis promotes memory CD8+ T cell longevity. Cell 161, 750–761 (2015).; O’Sullivan, D. et al. Memory CD8+ T cells use cell-intrinsic lipolysis to support the metabolic programming necessary for development. Immunity 41, 75–88 (2014).; Ringel, A. E. et al. Obesity shapes metabolism in the tumor microenvironment to suppress anti-tumor immunity. Cell 183, 1848–1866.e26 (2020).; Cases, S. et al. Identification of a gene encoding an acyl CoA: diacylglycerol acyltransferase, a key enzyme in triacylglycerol synthesis. Proc. Natl Acad. Sci. USA 95, 13018–13023 (1998).; Cases, S. et al. Cloning of DGAT2, a second mammalian diacylglycerol acyltransferase, and related family members. J. Biol. Chem. 276, 38870–38876 (2001). (PMID: 10.1074/jbc.M10621920011481335); Weisshaar, N. et al. Rgs16 promotes antitumor CD8+ T cell exhaustion. Sci. Immunol. 7, eabh1873 (2022).; Milner, J. J. et al. Heterogenous populations of tissue-resident CD8+ T cells are generated in response to infection and malignancy. Immunity 52, 808–824 (2020).; McLelland, G.-L. et al. Identification of an alternative triglyceride biosynthesis pathway. Nature 621, 171–178 (2023).; Lee, P. P. et al. A critical role for Dnmt1 and DNA methylation in T cell development, function, and survival. Immunity 15, 763–774 (2001). (PMID: 10.1016/S1074-7613(01)00227-811728338); Sawada, S., Scarborough, J. D., Killeen, N. & Littman, D. R. A lineage-specific transcriptional silencer regulates CD4 gene expression during T lymphocyte development. Cell 77, 917–929 (1994). (PMID: 10.1016/0092-8674(94)90140-68004678); Miller, B. C. et al. Subsets of exhausted CD8+ T cells differentially mediate tumor control and respond to checkpoint blockade. Nat. Immunol. 20, 326–336 (2019).; Kwon, H. et al. Androgen conspires with the CD8+ T cell exhaustion program and contributes to sex bias in cancer. Sci. Immunol. 7, eabq2630 (2022).; Yang, C. et al. Androgen receptor-mediated CD8+ T cell stemness programs drive sex differences in antitumor immunity. Immunity 55, 1268–1283 (2022).; Guan, X. et al. Androgen receptor activity in T cells limits checkpoint blockade efficacy. Nature 606, 791–796 (2022). (PMID: 10.1038/s41586-022-04522-63532223410294141); Guo, X. et al. Global characterization of T cells in non-small-cell lung cancer by single-cell sequencing. Nat. Med. 24, 978–985 (2018). (PMID: 10.1038/s41591-018-0045-329942094); Wagner, A. et al. Metabolic modeling of single Th17 cells reveals regulators of autoimmunity. Cell 184, 4168–4185.e21 (2021).; Spitler, K. M., Shetty, S. K., Cushing, E. M., Sylvers-Davie, K. L. & Davies, B. S. Regulation of plasma triglyceride partitioning by adipose-derived ANGPTL4 in mice. Sci. Rep. 11, 7873 (2021). (PMID: 10.1038/s41598-021-87020-5338464538041937); Gaud, C. et al. BioPAN: a web-based tool to explore mammalian lipidome metabolic pathways on LIPID MAPS. F1000Res. 10, 4 (2021).; Jain, I. H. et al. Genetic screen for cell fitness in high or low oxygen highlights mitochondrial and lipid metabolism. Cell 181, 716–727.e11 (2020).; Oh, M. et al. The lipoprotein-associated phospholipase A2 inhibitor Darapladib sensitises cancer cells to ferroptosis by remodelling lipid metabolism. Nat. Commun. 14, 5728 (2023). (PMID: 10.1038/s41467-023-41462-93771484010504358); Chen, X., Shi, C., He, M., Xiong, S. & Xia, X. Endoplasmic reticulum stress: molecular mechanism and therapeutic targets. Signal Transduct. Target. Ther. 8, 352 (2023). (PMID: 10.1038/s41392-023-01570-w3770977310502142); Sunryd, J. C. et al. TMTC1 and TMTC2 are novel endoplasmic reticulum tetratricopeptide repeat-containing adapter proteins involved in calcium homeostasis. J. Biol. Chem. 289, 16085–16099 (2014). (PMID: 10.1074/jbc.M114.554071247643054047382); Friedmann Angeli, J. P. et al. Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice. Nat. Cell Biol. 16, 1180–1191 (2014). (PMID: 10.1038/ncb3064254026834894846); Bengsch, B. et al. Bioenergetic insufficiencies due to metabolic alterations regulated by the inhibitory receptor PD-1 are an early driver of CD8+ T cell exhaustion. Immunity 45, 358–373 (2016).; Yu, Y.-R. et al. Disturbed mitochondrial dynamics in CD8+ TILs reinforce T cell exhaustion. Nat. Immunol. 21, 1540–1551 (2020).; Bantug, G. R. et al. Mitochondria-endoplasmic reticulum contact sites function as immunometabolic hubs that orchestrate the rapid recall response of memory CD8+ T cells. Immunity 48, 542–555 (2018).; Fransen, M., Nordgren, M., Wang, B. & Apanasets, O. Role of peroxisomes in ROS/RNS-metabolism: implications for human disease. Biochim. Biophys. Acta 1822, 1363–1373 (2012).; Di Cara, F. et al. Peroxisomes in immune response and inflammation. Int. J. Mol. Sci. 20, 3877 (2019). (PMID: 10.3390/ijms20163877313989436721249); Xu, F. et al. COPII mitigates ER stress by promoting formation of ER whorls. Cell Res. 31, 141–156 (2021).; Guo, Y. et al. Deep learning-based morphological classification of endoplasmic reticulum under stress. Front. Cell Dev. Biol. 9, 767866 (2022). (PMID: 10.3389/fcell.2021.767866352238638865080); Kim, J.-Y. et al. Obesity-associated improvements in metabolic profile through expansion of adipose tissue. J. Clin. Invest. 117, 2621–2637 (2007). (PMID: 10.1172/JCI31021177175991950456); Koliwad, S. K. et al. DGAT1-dependent triacylglycerol storage by macrophages protects mice from diet-induced insulin resistance and inflammation. J. Clin. Invest. 120, 756–767 (2010). (PMID: 10.1172/JCI36066201247292827941); Grbesa, I. et al. Reshaping of the androgen-driven chromatin landscape in normal prostate cells by early cancer drivers and effect on therapeutic sensitivity. Cell Rep. 36, 109625 (2021).; Hetz, C. The unfolded protein response: controlling cell fate decisions under ER stress and beyond. Nat. Rev. Mol. Cell Biol. 13, 89–102 (2012). (PMID: 10.1038/nrm327022251901); Song, M. et al. IRE1α–XBP1 controls T cell function in ovarian cancer by regulating mitochondrial activity. Nature 562, 423–428 (2018). (PMID: 10.1038/s41586-018-0597-x303057386237282); Hering, M. et al. Sphinganine recruits TLR4 adaptors in macrophages and promotes inflammation in murine models of sepsis and melanoma. Nat. Commun. 15, 6067 (2024). (PMID: 10.1038/s41467-024-50341-w3902585611258287); Ma, S. et al. Serine enrichment in tumors promotes regulatory T cell accumulation through sphinganine-mediated regulation of c-Fos. Sci. Immunol. 9, eadg8817 (2024). (PMID: 10.1126/sciimmunol.adg881738640251); Mekada, K. et al. Genetic differences among C57BL/6 substrains. Exp. Anim. 58, 141–149 (2009). (PMID: 10.1538/expanim.58.14119448337); Zurita, E. et al. Genetic polymorphisms among C57BL/6 mouse inbred strains. Transgenic Res. 20, 481–489 (2011).; Long, L. L. et al. Shared and distinctive features of the gut microbiome of C57BL/6 mice from different vendors and production sites, and in response to a new vivarium. Lab Anim. 50, 185–195 (2021).; Ericsson, A. C. & Franklin, C. L. The gut microbiome of laboratory mice: considerations and best practices for translational research. Mamm. Genome 32, 239–250 (2021). (PMID: 10.1007/s00335-021-09863-7336890008295156); Ivanov, I. I. et al. Induction of intestinal Th17 cells by segmented filamentous bacteria. Cell 139, 485–498 (2009). (PMID: 10.1016/j.cell.2009.09.033198360682796826); Pernigoni, N. et al. Commensal bacteria promote endocrine resistance in prostate cancer through androgen biosynthesis. Science 374, 216–224 (2021). (PMID: 10.1126/science.abf840334618582); Buchholz, V. R. et al. Disparate individual fates compose robust CD8+ T cell immunity. Science 340, 630–635 (2013).; Liu, K., Zhao, C., Adajar, R. C., DeZwaan-McCabe, D. & Rutkowski, D. T. A beneficial adaptive role for CHOP in driving cell fate selection during ER stress. EMBO Rep. 25, 228–253 (2024).; Wilcock, D. J. et al. Oxidative stress from DGAT1 oncoprotein inhibition in melanoma suppresses tumor growth when ROS defenses are also breached. Cell Rep. 39, 110995 (2022).; Vaughan, M. The production and release of glycerol by adipose tissue incubated in vitro. J. Biol. Chem. 237, 3354–3358 (1962). (PMID: 10.1016/S0021-9258(19)70821-713996476); Jensen, M. D., Ekberg, K. & Landau, B. R. Lipid metabolism during fasting. Am. J. Physiol. 281, E789–E793 (2001).; Chitraju, C. et al. Triglyceride synthesis by DGAT1 protects adipocytes from lipid-induced ER stress during lipolysis. Cell Metab. 26, 407–418 (2017).; Cheng, X. et al. Targeting DGAT1 ameliorates glioblastoma by increasing fat catabolism and oxidative stress. Cell Metab. 32, 229–242 (2020).; Xiong, L. et al. Direct androgen receptor control of sexually dimorphic gene expression in the mammalian kidney. Dev. Cell https://doi.org/10.1016/j.devcel.2023.08.010 (2023).; Castoldi, A. et al. Triacylglycerol synthesis enhances macrophage inflammatory function. Nat. Commun. 11, 4107 (2020). (PMID: 10.1038/s41467-020-17881-3327968367427976); Howie, D. et al. A novel role for triglyceride metabolism in Foxp3 expression. Front. Immunol. 10, 1860 (2019). (PMID: 10.3389/fimmu.2019.01860314568006701200); Graham, K. L. et al. DGAT1 inhibits retinol-dependent regulatory T cell formation and mediates autoimmune encephalomyelitis. Proc. Natl Acad. Sci. USA 116, 3126–3135 (2019).; Al-Habsi, M. et al. Spermidine activates mitochondrial trifunctional protein and improves antitumor immunity in mice. Science 378, eabj3510 (2022). (PMID: 10.1126/science.abj351036302005); Pircher, H., Bürki, K., Lang, R., Hengartner, H. & Zinkernagel, R. M. Tolerance induction in double specific T-cell receptor transgenic mice varies with antigen. Nature 342, 559–561 (1989). (PMID: 10.1038/342559a02573841); Chakraborty, P. et al. Androgen-dependent sertoli cell tight junction remodeling is mediated by multiple tight junction components. Mol. Endocrinol. 28, 1055–1072 (2014). (PMID: 10.1210/me.2013-1134248253974075161); Prévost-Blondel, A. et al. Tumor-infiltrating lymphocytes exhibiting high ex vivo cytolytic activity fail to prevent murine melanoma tumor growth in vivo. J. Immunol. 161, 2187–2194 (1998). (PMID: 10.4049/jimmunol.161.5.21879725210); Madi, A. et al. CD8 agonism functionally activates memory T cells and enhances antitumor immunity. Int. J. Cancer 151, 797–808 (2022). (PMID: 10.1002/ijc.3405935499751) |
| Substance Nomenclature: | EC 2.3.1.20 (Diacylglycerol O-Acyltransferase); EC 2.3.1.20 (Dgat1 protein, mouse); 0 (Receptors, Androgen); 0 (Fatty Acids) |
| Entry Date(s): | Date Created: 20260321 Date Completed: 20260328 Latest Revision: 20260328 |
| Update Code: | 20260328 |
| DOI: | 10.1038/s42255-026-01462-7 |
| PMID: | 41862754 |
| Database: | MEDLINE |
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