USP22 orchestrates an NK-suppressive program for tumor immune evasion 2309931
Over the past 17 years, our laboratory has established USP22 as a key regulator of both oncogenic and immune-evasive programs. However, how USP22 drives dysfunction of natural killer (NK) cells and CD8+ T cells–the principal cytotoxic effectors of tumor control–remains poorly understood, despite their central role in tumor progression and immunotherapy resistance. We performed unbiased profiling of intratumoral immune cells and delineated USP22-driven immunosuppressive networks by integrating genetic, molecular, and immunological approaches with single-cell transcriptomic, epigenomic, and proteomic analyses. Using advanced bioinformatics and AI/ML methods, we defined a USP22-associated molecular signature that robustly predicts immunotherapeutic resistance in human tumors. We demonstrate that tumor cell—specific inhibition of USP22 markedly increased NK cell infiltration across multiple syngeneic tumor models. Mechanistically, USP22 enforces a tumor-intrinsic immunosuppressive program by suppressing IL-15 and tumor-attracting chemokines, including CXCL9, CXCL10, and CXCL11, while promoting expression of the immune checkpoint ligand CD155. At the molecular level, USP22 drives epigenetic silencing and stabilizes key negative regulatory signaling pathways that enable tumor immune evasion. Importantly, multiplex immunophenotyping revealed that high USP22 expression was associated with reduced NK and CD8+ T-cell abundance and resistance to anti—PD-1 therapy. Notably, pharmacological inhibition of USP22 using our second-generation inhibitor overcame immune checkpoint blockade resistance in preclinical cancer models. Our study identifies USP22 as a tumor-intrinsic suppressor of NK- and CD8+ T-cell—mediated antitumor immunity and reports a USP22-specific inhibitor with dual onco-targeting and immune-boosting activity, representing a first-in-class therapeutic strategy. IND-enabling studies are underway to advance this inhibitor toward clinical translation. R01CA257520, R01CA284740 and CA232347 Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)