RNF180 loss stabilizes BCAS4 to enhance PD-L1 expression and immune evasion in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide, and the regulation of immune evasion within the tumor microenvironment remains poorly understood. This study shows that breast carcinoma susceptibility protein 4 (BCAS4), not previously studied in HCC, is markedly upregulated in HCC tissues and associated with T cell exhaustion signatures and poor prognosis. BCAS4 enhances PD-L1 expression through NF-κB signaling, driving CD8+ T cell dysfunction and immune evasion. We identify RNF180 as an E3 ligase that binds BCAS4 and mediates its degradation via K48-linked ubiquitination; loss of RNF180 stabilizes BCAS4, amplifying NF-κB activation and PD-L1 upregulation. In vitro and in vivo experiments using a human peripheral blood mononuclear cell (PBMC)-reconstituted xenograft model confirmed that the RNF180-BCAS4 axis modulates CD8+ T cell infiltration and function and promotes tumor progression. Our findings uncover a previously unrecognized RNF180-BCAS4-PD-L1 axis driving immune evasion in HCC, establishing BCAS4 as a potential prognostic biomarker and therapeutic target for improving immunotherapy responses in HCC patients.