Abstract

T cell senescence causes T cell dysfunction in tumors, but its drivers are unclear. Here we found that protein overload in the tumor microenvironment (TME) induces T cell differentiation into effector memory T cells re-expressing CD45RA (TEMRA). TEMRA cells exhibit senescent-like features, including reduced proliferative capacity and expression of senescence-associated markers. Both CD4 + and CD8 + T cells activated under high protein-to-amino-acid-ratio conditions in vitro or within TME niches underwent enhanced TEMRA differentiation. Single-cell transcriptomics showed that protein overload co-activates terminal effector and senescence programs. Mechanistically, it disrupts proteostasis by inhibiting lysosomal and proteasomal degradation, triggering a maladaptive unfolded protein response (UPR) that drives TEMRA commitment. Exogenous amino acid supplementation prevented UPR activation and TEMRA differentiation. In humanized tumors, intra-tumoral amino-acid administration reduced TEMRA accumulation, boosted T cell proliferation, and improved tumor control. Our work reveals managing proteostatic stress as a strategy to counter TEMRA generation and restore anti-tumor immunity.