Proteotoxic stress response drives T cell exhaustion and immune evasion

作者：Yi Wang, Anjun Ma, No Joon Song, Ariana E. Shannon, Yaa S. Amankwah, Xingyu Chen, Weidong Wu, Ziyu Wang, Abbey A. Saadey, Amir Yousif, Gautam Ghosh, Jay K. Mandula, Maria Velegraki, Tong Xiao, Haitao Wen, Stanley Ching‐Cheng Huang, Ruoning Wang, Christian M. Beusch, Abdelhameed S. Dawood, David E. Gordon, Mohamed S. Abdel-Hakeem, Hazem E. Ghoneim, Gang Xin, Brian C. Searle, Zihai Li · 发表于：Nature · 年份：2025 · DOI：10.1038/s41586-025-09539-1 · 被引用次数：51 · 研究领域：Immune Cell Function and Interaction、CAR-T cell therapy research、Cancer Immunotherapy and Biomarkers

Chronic infections and cancer cause T cell dysfunction known as exhaustion. This cell state is caused by persistent antigen exposure, suboptimal co-stimulation and a plethora of hostile factors that dampen protective immunity and limit the efficacy of immunotherapies1–4. The mechanisms that underlie T cell exhaustion remain poorly understood. Here we analyse the proteome of CD8+ exhausted T (Tex) cells across multiple states of exhaustion in the context of both chronic viral infections and cancer. We show that there is a non-stochastic pathway-specific discordance between mRNA and protein dynamics between T effector (Teff) and Tex cells. We identify a distinct proteotoxic stress response (PSR) in Tex cells, which we term Tex-PSR. Contrary to canonical stress responses that induce a reduction in protein synthesis5,6, Tex-PSR involves an increase in global translation activity and an upregulation of specialized chaperone proteins. Tex-PSR is further characterized by the accumulation of protein aggregates and stress granules and an increase in autophagy-dominant protein catabolism. We establish that disruption of proteostasis alone can convert Teff cells to Tex cells, and we link Tex-PSR mechanistically to persistent AKT signalling. Finally, disruption of Tex-PSR-associated chaperones in CD8+ T cells improves cancer immunotherapy in preclinical models. Moreover, a high Tex-PSR in T cells from patients with cancer confers poor responses to clinical immunotherapy. Collectively, ou...