Proteomic atlas of T cell exhaustion defines proteostatic collapse.

Proteostatic collapse, marked by changes in ubiquitin-proteasome system and E3 ligases, is a key feature of T cell exhaustion in cancer immunotherapy.

• Why it matters: Understanding the molecular basis of T cell exhaustion is crucial for improving immunotherapy outcomes, as current knowledge of proteomic alterations remains limited.
• What they did: The study integrated transcriptomics, quantitative proteomics, turnover proteomics, and ubiquitin proteomics to create a multi-omic atlas of exhausted T cells, highlighting pathways involving ubiquitin modifications and proteostasis.
• The result: Overexpression of the E3 ligase RNF166 improved T cell persistence, suggesting that manipulating proteostasis regulators like E3 ligases could restore T cell function and enhance immunotherapy efficacy.