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<p>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<sup>+</sup> and CD8<sup>+</sup> T cells activated under high protein-to-amino-acid-ratio conditions <i>in vitro</i> 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.</p>

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Proteostasis Collapse Drives Effector Memory T Cells Re-expressing CD45RA (TEMRA) Generation in the Tumor Microenvironment

  • 期刊论文

  • 发表日期：

    2026年4月2日

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  • Linlin Li,
  • Shuo Kan,
  • Qiang Huang,
  • Shiwen Wang,
  • Yuchen Han,
  • Liang Chen,
  • Jun Jin

摘要

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.