Inhibition of Aurora B induces senescence and potentiates immunotherapy in hepatocellular carcinoma

BACKGROUND: Hepatocellular carcinoma (HCC) is a global health challenge, with limited treatment options for advanced-stage patients. Although recent approvals of targeted therapies and immune checkpoint inhibitors (ICIs) have expanded the therapeutic landscape, their clinical benefits are often constrained by modest response rates and acquired resistance. Despite ongoing efforts to identify new therapeutic targets, only few inhibitors have progressed to clinical trials, benefiting a small subset of patients. These limitations underscore the need for more effective therapeutic strategies. METHODS: We integrated data from DepMap and TCGA to identify HCC-specific vulnerabilities. A kinome-wide CRISPR screen validated essential targets. Pharmacological inhibition (AZD1152) and genetic knockout of Aurora B (AURKB) were employed for functional validation. Senescence was assessed via SA-β-gal staining, transcriptomics, and SASP analysis. Immune interactions were evaluated using co-culture assays with T cells and flow cytometry for MHC I and immune markers. In vivo efficacy was tested in immunocompetent murine HCC models. RESULTS: Aurora B was identified as a top candidate essential for HCC survival, overexpressed in tumors, and correlated with poor prognosis. A kinome-wide CRISPR screen further confirmed its essential role in HCC cell survival. Pharmacologic inhibition or genetic knockout of Aurora B markedly suppressed proliferation of HCC cells and induced robust cellular senescence, characterized by cell-cycle arrest, DNA damage, and SASP. These senescent cells exhibited heightened susceptibility to T-cell-mediated cytotoxicity, associated with increased immunoproteasome activity and upregulated MHC I expression. Co-culture assays revealed that senescent tumor cells promoted interferon-γ production and enhanced cytotoxicity in CD8⁺ T cells as well as PD-1 expression. In both in vitro and in vivo models, combining Aurora B inhibition with anti-PD-1 therapy markedly suppressed tumor growth. CONCLUSION: This study identifies Aurora B as a therapeutically actionable vulnerability in HCC, whose inhibition induces senescence and enhances tumor immunogenicity. The combination of Aurora B inhibitor with anti-PD-1 therapy yields synergistic anti-tumor effects, supporting its potential as a promising strategy to improve immunotherapy outcomes in HCC.