Deubiquitinase USP24 activated by IL-6/STAT3 enhances PD-1 protein stability and suppresses T cell antitumor response

• DOI: 10.1126/sciadv.adt4258
• Publication Date: 2025-04-16T17:58:56Z
• Authors: Hung-Chia Hsieh; Ming-Jer Young; Kuan-Yu Chen; Wu-Chou Su; Chien-Chung Lin; Yi-Ting Yen; Jan-Jong Hung; Yi-Ching Wang
• Keywords: Cancer Immunotherapy

Persisting programmed cell death-1 (PD-1) signaling impairs T effector function, which is highly associated with exhaustion and immunotherapy failure. However, the mechanism responsible for PD-1 deubiquitination dysfunction remains unclear. Here, we show that ubiquitin-specific peptidase 24 (USP24) promotes protein stability by removing K48-linked polyubiquitin. Increased interleukin-6 level transcriptionally activates USP24 expression, leads to stabilization. Furthermore, deficiency reduces levels in CD8 + cells attenuates Egfr L858R -driven lung tumorigenesis Usp24 C1695A catalytic deficient mice. Targeting USP24-specific inhibitor USP24-i-101 boosts cytotoxic activity, restrains tumor growth, achieves superior therapeutic effects when combined anti-CTLA4 immunotherapy. Clinically, patients cancer exhibiting high expression tumor-infiltrating display exhausted features unfavorable responses Our findings dissect regulating enhanced reveal as a potential target of antitumor