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 immunotherapies^1-4. The mechanisms that underlie T cell exhaustion remain poorly understood. Here we analyse the proteome of CD8⁺ exhausted T (T_ex) 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 (T_eff) and T_ex cells. We identify a distinct proteotoxic stress response (PSR) in T_ex cells, which we term T_ex-PSR. Contrary to canonical stress responses that induce a reduction in protein synthesis^5,6, T_ex-PSR involves an increase in global translation activity and an upregulation of specialized chaperone proteins. T_ex-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 T_eff cells to T_ex cells, and we link T_ex-PSR mechanistically to persistent AKT signalling. Finally, disruption of T_ex-PSR-associated chaperones in CD8⁺ T cells improves cancer immunotherapy in preclinical models. Moreover, a high T_ex-PSR in T cells from patients with cancer confers poor responses to clinical immunotherapy. Collectively, our findings indicate that T_ex-PSR is a hallmark and a mechanistic driver of T cell exhaustion, which raises the possibility of targeting proteostasis pathways as an approach for cancer immunotherapy.

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