A deubiquitination module essential for T_reg fitness in the tumor microenvironment

The tumor microenvironment (TME) enhances regulatory T (T_reg) cell stability and immunosuppressive functions through up-regulation of lineage transcription factor Foxp3, a phenomenon known as T_reg fitness or adaptation. Here, we characterize previously unknown TME-specific cellular and molecular mechanisms underlying T_reg fitness. We demonstrate that TME-specific stressors including transforming growth factor-β (TGF-β), hypoxia, and nutrient deprivation selectively induce two Foxp3-specific deubiquitinases, ubiquitin-specific peptidase 22 (Usp22) and Usp21, by regulating TGF-β, HIF, and mTOR signaling, respectively, to maintain T_reg fitness. Simultaneous deletion of both USPs in T_reg cells largely diminishes TME-induced Foxp3 up-regulation, alters T_reg metabolic signatures, impairs T_reg-suppressive function, and alleviates T_reg suppression on cytotoxic CD8⁺ T cells. Furthermore, we developed the first Usp22-specific small-molecule inhibitor, which dramatically reduced intratumoral T_reg Foxp3 expression and consequently enhanced antitumor immunity. Our findings unveil previously unappreciated mechanisms underlying T_reg fitness and identify Usp22 as an antitumor therapeutic target that inhibits T_reg adaptability in the TME.