SOCS5 suppresses antitumor immunity in colorectal cancer by promoting IFNAR1 ubiquitylation and type I interferon response.

Colorectal cancer (CRC) is a highly prevalent malignancy with limited treatment options for advanced stages, and immune checkpoint blockade (ICB) efficacy is restricted by primary or acquired resistance. This study investigated the role of suppressor of cytokine signaling 5 (SOCS5) in CRC progression and immune evasion. We found SOCS5 is overexpressed in CRC tissues and correlates with poor patient prognosis. Functionally, SOCS5 does not affect CRC cell proliferation but impairs anti-tumor CD8+ T-cell immunity by negatively regulating type I interferon (IFN-I) signaling. Mechanistically, SOCS5 acts as an E3 ubiquitin ligase to promote K48-linked ubiquitination and degradation of IFNAR1, inhibiting IFN-I pathway activation. Furthermore, high SOCS5 expression is associated with reduced ICB response in CRC patients, and targeting SOCS5 enhances the efficacy of anti-PD-1 therapy in preclinical models by boosting CD8+ T-cell-mediated anti-tumor immunity. These findings identify SOCS5 as a novel prognostic biomarker and therapeutic target to improve ICB outcomes in CRC.