A deubiquitination module essential for T reg fitness in the tumor microenvironment.

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