Proteasome-guided haem signalling axis contributes to T cell exhaustion

Article Article scientifique Article Proteasome-guided haem signalling axis contributes to T cell exhaustion eng 2026-03-18 2026-05 author Xu Yingxi 0000-0002-0056-7440 Department of Oncology, University of Lausanne, Lausanne, Switzerland. xuyingxi@ihcams.ac.cn.,Ludwig Institute for Cancer Research Lausanne branch, Lausanne, Switzerland. xuyingxi@ihcams.ac.cn.,State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China. xuyingxi@ihcams.ac.cn.,Tianjin Institutes of Health Science, Tianjin, China. xuyingxi@ihcams.ac.cn. author Shangguan Yangtao State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China.,Tianjin Institutes of Health Science, Tianjin, China. author Chuang Yu-Ming Department of Oncology, University of Lausanne, Lausanne, Switzerland.,Ludwig Institute for Cancer Research Lausanne branch, Lausanne, Switzerland. author Chang Tzu-Hsuan 0000-0003-0455-3107 Department of Oncology, University of Lausanne, Lausanne, Switzerland.,Ludwig Institute for Cancer Research Lausanne branch, Lausanne, Switzerland. author Liu Wenbing 0000-0003-4562-5541 State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China.,Tianjin Institutes of Health Science, Tianjin, China. author Peng Jhan-Jie Department of Oncology, University of Lausanne, Lausanne, Switzerland.,Ludwig Institute for Cancer Research Lausanne branch, Lausanne, Switzerland.,Graduate Institute of Clinical Medical Sciences, Chang Gung University, Taoyuan, Taiwan.,Center for Molecular and Clinical Immunology, Chang Gung University, Taoyuan, Taiwan. author Garnica Caparros Josep 0000-0001-9493-1321 Department of Oncology, University of Lausanne, Lausanne, Switzerland.,Ludwig Institute for Cancer Research Lausanne branch, Lausanne, Switzerland.,Swiss Institute of Bioinformatics, Lausanne, Switzerland. 440383 author Xie Leling State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China.,Tianjin Institutes of Health Science, Tianjin, China. author Hsueh Pei-Chun Department of Oncology, University of Lausanne, Lausanne, Switzerland.,Ludwig Institute for Cancer Research Lausanne branch, Lausanne, Switzerland. author Lin Mei-Chun Department of Oncology, University of Lausanne, Lausanne, Switzerland.,Ludwig Institute for Cancer Research Lausanne branch, Lausanne, Switzerland.,Department of Otolaryngology, National Taiwan University Hospital, Taipei, Taiwan. author Wang Yi-Hao 0009-0004-3972-4206 Department of Oncology, University of Lausanne, Lausanne, Switzerland.,Ludwig Institute for Cancer Research Lausanne branch, Lausanne, Switzerland. author Hajdu Karina Lobo 0000-0001-9655-3870 Department of Oncology, University of Lausanne, Lausanne, Switzerland.,Ludwig Institute for Cancer Research Lausanne branch, Lausanne, Switzerland. author Wu Yibo Chemical Biology Mass Spectrometry Platform (CHEMBIOMS), Faculty of Sciences, University of Geneva, Geneva, Switzerland.,Department of Biomedical Sciences, University of Lausanne, Lausanne, Switzerland. 969931 author Akrami Maryam 0000-0001-6450-8442 Laboratory of Cancer Immunology, Department of Biomedicine, University of Basel and University Hospital of Basel, Basel, Switzerland. author Wang Chen 0000-0003-2271-5587 Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland.,Geneva Centre for Inflammation Research, Geneva, Switzerland.,National Key Laboratory of Immunity and Inflammation, Suzhou Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou, China. 894272 author Kohl Anna Department of Oncology, University of Lausanne, Lausanne, Switzerland.,Ludwig Institute for Cancer Research Lausanne branch, Lausanne, Switzerland. author Zippelius Alfred 0000-0003-1933-8178 Laboratory of Cancer Immunology, Department of Biomedicine, University of Basel and University Hospital of Basel, Basel, Switzerland.,Medical Oncology, University Hospital Basel, Basel, Switzerland. author Qi Wei Novogene Co. Ltd, Beijing, China. author Wang Min State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China.,Tianjin Institutes of Health Science, Tianjin, China. author Budiarto Bugi Ratno Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.,Taiwan International Graduate Program in Molecular Medicine, National Yang Ming Chiao Tung University and Academia Sinica, Taipei, Taiwan. author Chen Shih-Yu 0000-0002-7955-481X Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan. author Xiao Zhengtao School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, China. author Vardaka Panagiota Department of Pathology, University of Cambridge, Cambridge, UK.,Laboratory of Lymphocyte Signaling and Development, Babraham Institute, Cambridge, UK. author Roychoudhuri Rahul 0000-0002-5392-1853 Department of Pathology, University of Cambridge, Cambridge, UK.,Laboratory of Lymphocyte Signaling and Development, Babraham Institute, Cambridge, UK. author Bai Zhiliang 0000-0002-3977-3057 Department of Biomedical Engineering, Yale University, New Haven, CT, USA. author Fan Rong 0000-0001-7805-8059 Department of Biomedical Engineering, Yale University, New Haven, CT, USA. author Carmona Santiago 0000-0002-2495-0671 Department of Oncology, University of Lausanne, Lausanne, Switzerland.,Ludwig Institute for Cancer Research Lausanne branch, Lausanne, Switzerland.,Swiss Institute of Bioinformatics, Lausanne, Switzerland. 433334 Département de pathologie et immunologie (PATIM) author Yu Yi-Ru Department of Oncology, University of Lausanne, Lausanne, Switzerland.,Ludwig Institute for Cancer Research Lausanne branch, Lausanne, Switzerland. author Scheiermann Christoph 0000-0002-9212-0995 Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland.,Geneva Centre for Inflammation Research, Geneva, Switzerland. 891044 Département de pathologie et immunologie (PATIM) author Wang Jianxiang 0000-0001-9437-9151 State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China. wangjx@ihcams.ac.cn.,Tianjin Institutes of Health Science, Tianjin, China. wangjx@ihcams.ac.cn. author Ho Ping-Chih 0000-0003-3078-3774 Department of Oncology, University of Lausanne, Lausanne, Switzerland. ping-chih.ho@unil.ch.,Ludwig Institute for Cancer Research Lausanne branch, Lausanne, Switzerland. ping-chih.ho@unil.ch.,College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan. ping-chih.ho@unil.ch. 548-557 10.1038/s41586-026-10250-y 41851457 0028-0836 PMC13658038 https://www.nature.com/articles/s41586-026-10250-y The accumulation of depolarized mitochondria commits T cells to exhaustion1-3 , yet the precise mechanism remains unclear. Here we find that exhausted CD8+ T cells increase proteasome activity owing to the accumulation of depolarized mitochondria, which drives the selective degradation of mitochondrial proteins and the release of regulatory haem through haemoprotein breakdown. In turn, increased regulatory haem disrupts BACH2-mediated transcriptional regulation, thereby exacerbating T cell exhaustion and compromising stemness-like properties. Inhibition of nuclear import of regulatory haem prevents BACH2 degradation and enhances the anti-tumour efficacy of antigen-specific T cells. We find that the therapeutic efficacy of human CD19+ chimeric antigen receptor (CAR)-T cells in patients with B cell acute lymphoblastic leukaemia negatively correlates with the proteasome gene signature in their CAR-T cells. Manufacturing CAR-T cells in the presence of bortezomib, an FDA-approved proteasome inhibitor, prevents T cell exhaustion and improves therapeutic efficacy. Our findings identify a proteasome-guided haem signalling axis, governed by mitochondrial integrity, as a regulator of CD8+ T cell exhaustion and propose innovative therapeutic strategies that exploit this pathway to optimize adoptive cellular immunotherapy. Humans Proteasome Endopeptidase Complex / metabolism Proteasome Endopeptidase Complex / genetics Mitochondria / metabolism Mitochondria / drug effects Mitochondria / pathology Signal Transduction / drug effects CD8-Positive T-Lymphocytes / immunology CD8-Positive T-Lymphocytes / cytology CD8-Positive T-Lymphocytes / metabolism CD8-Positive T-Lymphocytes / drug effects Bortezomib / pharmacology Animals Heme / metabolism Mice Immunotherapy, Adoptive Receptors, Chimeric Antigen / immunology Receptors, Chimeric Antigen / metabolism Female Male Proteolysis / drug effects Mitochondrial Proteins / metabolism Proteasome Inhibitors / pharmacology Precursor Cell Lymphoblastic Leukemia-Lymphoma / immunology Precursor Cell Lymphoblastic Leukemia-Lymphoma / therapy Precursor Cell Lymphoblastic Leukemia-Lymphoma / pathology T-Cell Exhaustion Dewey 500 Dewey 616.07 Swiss National Science Foundation Harnessing Kupffer cells and cytokine signaling to tailor T cell differentiation for treating hepatocellular carcinomas 215126 CH Swiss National Science Foundation Delineate common cellular circuits that orchestrate T cell immunity in chronic infections and tumors 208130 CH Swiss National Science Foundation Dissecting the non-canonical role of IL-4 in macrophage polarization 206083 CH Swiss National Science Foundation Exploiting regulatory circuits guiding tissue context- and metabolism-dependent differentiation program of T cell exhaustion in tumors and chronic viral infection 205930 CH Swiss National Science Foundation Modulating mitochondria-mediated regulations to tailor T cell anti-tumor responses 213736 CH 137 Département de pathologie et immunologie 21F 2 Faculté des sciences 1 false 1259 L'influence du rôle du cycle circadien sur l'immunité 995 1459 Science des données "-omiques" à l'échelle de la cellule unique pour le cancer et l'immunologie 1071 Nature 653 8114 190faa8c-5ce1-4250-8e77-213898fa66f3 Article (Published version) Public Xu_et_al_Nature_2026.pdf 15055558 application/pdf OA OTHER 88695ea38205ef48ecf7de7667d1625f59cdef14c9b7cdb95eb84806adbce2a0 a8554984-42da-4bed-824e-7602d0b8cf34 Corrigendum Public s41586-026-10608-2.pdf 614829 application/pdf 5788b093b2fcfda8e5059a6027ec733b24d88ec3c3eb6ba843181d848919bcaf d7e3cae2-7340-4637-a521-d01f1f845a47 Corrigendum Public s41586-026-11083-5.pdf 593624 application/pdf 4d9832cf389d1c4a2b4df805b9815c00b92266359a7a725ffe3d168281cd62fc In the version of this article initially published, there were errors in the first paragraph of the “Haem directs T cell fate through BACH2” section, where citations to Fig. 3b,c, Fig. 3e, Fig. 3f,g, Fig. 3g and Fig. 3h originally cited Fig. 4b,c, Fig. 4e, Fig. 4f,g, Fig. 4g and Fig. 4h, respectively. In Fig. 3d,f–h, the current colour keys (Bach2WT in purple, Bach2MUT in blue) were originally reversed owing to removal of a figure from the last revised version. In addition, the Source Data file associated with Fig. 5j contained a copy-and-paste error. The text, figure and source data are now amended in the HTML and PDF versions of the article. 10.1038/s41586-026-10608-2 42098307 In the version of the article initially published, there were several copy–paste errors in the source data for Figs. 1p, 3h and Extended Data Fig. 3c. Figure 1p and Extended Data Fig. 3c have been updated as a result and the original figures are available for comparison as Supplementary information accompanying this amendment. Additionally, since the “FOXO1” results were not included in Extended Data Fig. 3a, the data have been removed from the source data file. These corrections have been made to the HTML and PDF versions of the article. 10.1038/s41586-026-11083-5 42811125 openAccess Faculté de médecine / Section de médecine fondamentale / Département de pathologie et immunologie Faculté des sciences

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Proteasome-guided haem signalling axis contributes to T cell exhaustion	Nature	2026	2	0
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