Enhancing Proteasome Activity in T Cells Alleviates Exhaustion and Improves Antitumor Immunity.

Chronic T-cell receptor (TCR) stimulation combined with adverse conditions in the tumor microenvironment (TME), such as hypoxia and nutrient deprivation, frequently results in T-cell exhaustion. Exhausted CD8+ T cells (TEX) experience oxidative stress, which causes an accumulation of oxidized proteins within the cells. We hypothesized that oxidized protein formation might exceed proteasomal degradation capacity, leading to their accumulation and impairing T-cell fitness. Single-cell transcriptomics analysis across 16 tumor types revealed increased expression of proteasome genes in TEX compared with non-TEX. In a robust in vitro model for the generation of human TEX, the cells exhibited hallmarks of exhaustion, with higher levels of reactive oxygen species-induced protein oxidation and increased expression of proteasome genes. Pharmacologic and genetic enhancement of proteasome activity delayed the onset of T-cell exhaustion, improved T-cell fitness, and translated into superior antitumor immunity and tumor control. These findings identify proteasome modulation as a promising strategy to counteract TME-driven T-cell dysfunction, potentially overcoming a major obstacle to the efficacy of cell-based immunotherapies in solid tumors. SIGNIFICANCE: Increased proteasome activity serves as a compensatory mechanism to manage oxidative stress, alleviate proteotoxicity, and prevent exhaustion in T cells, offering opportunities for cancer immunotherapy.