This paper reports on the discovery of a distinct mechanism driving T cell exhaustion (Tex cells) in the context of chronic infections and cancer. The authors utilized proteomic analysis to identify a unique cellular stress response, termed Tex-PSR (proteotoxic stress response), which is characterized by an unusual increase in global protein synthesis and the accumulation of protein aggregates, despite increased protein degradation. Furthermore, the research establishes that this proteotoxic stress can causally drive T cell exhaustion even without persistent T cell receptor stimulation, and links Tex-PSR to sustained AKT signaling. Crucially, targeting associated Tex-PSR chaperone proteins (like BiP and gp96) in preclinical models was shown to improve cancer immunotherapy outcomes, suggesting a new therapeutic target for overcoming resistance to current treatments like immune checkpoint blockade.

References:

• Wang Y, Ma A, Song N J, et al. Proteotoxic stress response drives T cell exhaustion and immune evasion[J]. Nature, 2025: 1-11.