Ubiquitin ligase STUB1 destabilizes IFN gamma-receptor complex to suppress tumor IFN gamma signaling

The cytokine IFN gamma differentially impacts on tumors upon immune checkpoint blockade (ICB). Despite our understanding of downstream signaling events, less is known about regulation of its receptor (IFN gamma-R1). With an unbiased genome-wide CRISPR/Cas9 screen for critical regulators of IFN gamma-R1 cell surface abundance, we identify STUB1 as an E3 ubiquitin ligase for IFN gamma-R1 in complex with its signal-relaying kinase JAK1. STUB1 mediates ubiquitination-dependent proteasomal degradation of IFN gamma-R1/JAK1 complex through IFN gamma-R1(K285) and JAK1(K249). Conversely, STUB1 inactivation amplifies IFN gamma signaling, sensitizing tumor cells to cytotoxic T cells in vitro. This is corroborated by an anticorrelation between STUB1 expression and IFN gamma response in ICB-treated patients. Consistent with the context-dependent effects of IFN gamma in vivo, anti-PD-1 response is increased in heterogenous tumors comprising both wildtype and STUB1-deficient cells, but not full STUB1 knockout tumors. These results uncover STUB1 as a critical regulator of IFN gamma-R1, and highlight the context-dependency of STUB1-regulated IFN gamma signaling for ICB outcome. The IFN gamma response pathway is associated with response to immunotherapy in cancer. Here the authors show that high levels of the IFN gamma-receptor (IFN gamma-R1) affect the outcome of immunotherapy in a context-dependent fashion and identify the E3 ubiquitin ligase STUB1 as a negative regulator of IFN gamma-R1/JAK1 expression in cancer cells.