Proteasome-guided haem signalling axis contributes to T cell exhaustion PMID: 41851457

ADC Targets in Oncology

2026-04-10

Proteasome-guided haem signalling axis contributes to T cell exhaustion

Nature. 2026 May;653(8114):548-557. doi: 10.1038/s41586-026-10250-y.

Yingxi Xu ¹ ² ³ ⁴ , Yangtao Shangguan ⁵ ⁶ , Yu-Ming Chuang ⁷ ⁸ , Tzu-Hsuan Chang ⁷ ⁸ , Wenbing Liu ⁵ ⁶ , Jhan-Jie Peng ⁷ ⁸ ⁹ ¹⁰ , Josep Garnica ⁷ ⁸ ¹¹ , Leling Xie ⁵ ⁶ , Pei-Chun Hsueh ⁷ ⁸ , Mei-Chun Lin ⁷ ⁸ ¹² , Yi-Hao Wang ⁷ ⁸ , Karina Lobo Hajdu ⁷ ⁸ , Yibo Wu ¹³ ¹⁴ , Maryam Akrami ¹⁵ , Chen Wang ¹⁶ ¹⁷ ¹⁸ , Anna Kohl ⁷ ⁸ , Alfred Zippelius ¹⁵ ¹⁹ , Wei Qi ²⁰ , Min Wang ⁵ ⁶ , Bugi Ratno Budiarto ²¹ ²² , Shih-Yu Chen ²¹ , Zhengtao Xiao ²³ , Panagiota Vardaka ²⁴ ²⁵ , Rahul Roychoudhuri ²⁴ ²⁵ , Zhiliang Bai ²⁶ , Rong Fan ²⁶ , Santiago Carmona ⁷ ⁸ ¹¹ , Yi-Ru Yu ⁷ ⁸ , Christoph Scheiermann ¹⁶ ¹⁷ , Jianxiang Wang ²⁷ ²⁸ , Ping-Chih Ho ²⁹ ³⁰ ³¹

Affiliations

1. Department of Oncology, University of Lausanne, Lausanne, Switzerland. [email protected].
2. Ludwig Institute for Cancer Research Lausanne branch, Lausanne, Switzerland. [email protected].
3. 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. [email protected].
4. Tianjin Institutes of Health Science, Tianjin, China. [email protected].
5. 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.
6. Tianjin Institutes of Health Science, Tianjin, China.
7. Department of Oncology, University of Lausanne, Lausanne, Switzerland.
8. Ludwig Institute for Cancer Research Lausanne branch, Lausanne, Switzerland.
9. Graduate Institute of Clinical Medical Sciences, Chang Gung University, Taoyuan, Taiwan.
10. Center for Molecular and Clinical Immunology, Chang Gung University, Taoyuan, Taiwan.
11. Swiss Institute of Bioinformatics, Lausanne, Switzerland.
12. Department of Otolaryngology, National Taiwan University Hospital, Taipei, Taiwan.
13. Chemical Biology Mass Spectrometry Platform (CHEMBIOMS), Faculty of Sciences, University of Geneva, Geneva, Switzerland.
14. Department of Biomedical Sciences, University of Lausanne, Lausanne, Switzerland.
15. Laboratory of Cancer Immunology, Department of Biomedicine, University of Basel and University Hospital of Basel, Basel, Switzerland.
16. Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland.
17. Geneva Centre for Inflammation Research, Geneva, Switzerland.
18. National Key Laboratory of Immunity and Inflammation, Suzhou Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou, China.
19. Medical Oncology, University Hospital Basel, Basel, Switzerland.
20. Novogene Co. Ltd, Beijing, China.
21. Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
22. Taiwan International Graduate Program in Molecular Medicine, National Yang Ming Chiao Tung University and Academia Sinica, Taipei, Taiwan.
23. School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, China.
24. Department of Pathology, University of Cambridge, Cambridge, UK.
25. Laboratory of Lymphocyte Signaling and Development, Babraham Institute, Cambridge, UK.
26. Department of Biomedical Engineering, Yale University, New Haven, CT, USA.
27. 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. [email protected].
28. Tianjin Institutes of Health Science, Tianjin, China. [email protected].
29. Department of Oncology, University of Lausanne, Lausanne, Switzerland. [email protected].
30. Ludwig Institute for Cancer Research Lausanne branch, Lausanne, Switzerland. [email protected].
31. College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan. [email protected].

Abstract

The accumulation of depolarized mitochondria commits T cells to exhaustion^1-3, 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.