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 <i>Egfr^L858R</i>-driven lung tumorigenesis in <i>Usp24^C1695A</i> catalytic deficient mice. Targeting PD-1 stability with the USP24-specific inhibitor USP24-i-101 boosts cytotoxic T cell activity, restrains lung tumor growth, and achieves superior therapeutic effects when combined with anti-CTLA4 immunotherapy. Clinically, patients with lung cancer exhibiting high USP24 expression in tumor-infiltrating CD8⁺ T cells display exhausted features and show unfavorable responses to immunotherapy. Our findings dissect the mechanism for regulating enhanced PD-1 stability in tumor-infiltrating CD8⁺ T cells and reveal USP24 as a potential target of antitumor immunotherapy.