Persistent antigen exposure, such as in chronic infections and cancer, induces hypofunctional T cells known as exhausted T (Tex) cells. However, the mechanisms that underlie the development of this cell state are poorly understood. By analysing the proteome of CD8+ T cells at different stages of exhaustion in both infection and cancer, Li and colleagues identified a distinct proteotoxic stress response (PSR) in Tex cells, termed Tex-PSR. It is characterized by a pathway-specific discordance between transcript and protein levels, a global increase in translation and an accumulation of protein aggregates, and was linked to persistent AKT signalling. The introduction of misfolded proteins into CD8+ T cells, even without continuous T cell receptor stimulation, triggered Tex-PSR and T cell exhaustion. They also noted a selective upregulation of chaperone proteins, and the disruption of these chaperones in CD8+ T cells improved their antiviral and anticancer properties in mouse models. In patients with cancer, a high Tex-PSR was linked to poor responses to immunotherapy. These results raise the possibility of targeting dysregulated proteostasis to enhance cancer immunotherapy.