STUB1 dampens IFN? response in tumors by destabilizing the IFN? receptor complex

Despite its success, immune checkpoint blockade (ICB) cannot induce durable responses in most patients. This is partially attributed to reduced sensitivity to interferon gamma (IFN?). Thus, elevating tumor IFN?-receptor 1 (IFN?-R1) expression to enhance IFN?-mediated cytotoxicity is of clinical interest. Here, we demonstrate higher IFN?-R1 expression to sensitize tumors to IFN?-mediated killing. To unveil the largely undefined mechanisms of IFN?-R1 expression, we performed a genome-wide CRISPR/Cas9 knockout screen for suppressors of IFN?-R1 tumor cell surface abundance. We uncovered STUB1 as key mediator for proteasomally degrading IFN?-R1/JAK1 complex. Conversely, STUB1 inactivation in tumor cells amplified IFN? signaling and sensitized to cytotoxic T cells, but permitted IFN?-induced PD-L1 expression. Rationally combining STUB1 inactivation with anti-PD-1 treatment effectively eliminated tumors in vivo. Clinically corroborating this is a STUB1 transcriptomic signature that associates with response to anti-PD-1 treatment in two patient cohorts. Thus, uncovering STUB1 as a pivotal regulator of IFN? signaling and a synergistic target for anti-PD-1 treatment. Overall design: Human melanoma cell lines (Control or with STUB1 knock-out) were grown in the presence of Tcell, IFNgamma or control. Three timepoints were taken, 0 hours, 4 hours and 8 hours.