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.