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

ABSTRACT: Persisting programmed cell death-1 (PD-1) signaling impairs T cell effector function, which is highly associated with T cell exhaustion and immunotherapy failure. However, the mechanism responsible for PD-1 deubiquitination and T cell dysfunction remains unclear. Here, we show that ubiquitin-specific peptidase 24 (USP24) promotes PD-1 protein stability by removing K48-linked polyubiquitin. Increased interleukin-6 level transcriptionally activates the USP24 expression, which leads to PD-1 stabilization. Furthermore, USP24 deficiency reduces PD-1 levels in CD8⁺ T cells and attenuates Egfr^L858R-driven lung tumorigenesis in Usp24^C1695A catalytic deficient mice. Targeting PD-1 stability with the USP24-specific inhibitor USP24-i-101 boosts cytotoxic

SUBMITTER: Hsieh HC 

PROVIDER: S-EPMC12002121 | biostudies-literature | 2025 Apr

REPOSITORIES: biostudies-literature