Histone methyl-transferase G9a inhibition boosts the efficacy of immune checkpoint inhibitors in experimental hepatocellular carcinoma

Immune checkpoint inhibitors (ICIs) transform cancer therapy, but their efficacy in hepatocellular carcinoma (HCC) remains limited due to tumor-intrinsic immune evasion. We investigate the epigenetic regulator G9a (EHMT2) as a driver of immune resistance and evaluate pharmacologic inhibition as a therapeutic strategy. G9a expression is analyzed across human HCC cohorts and correlated with transcriptomic signatures predictive of ICI response. Using human and murine HCC cell lines and immunocompetent mouse models, we assess the antitumor effects of two G9a inhibitors, CM272 and EZM8266, combined with anti-PD1 therapy. Elevated G9a expression inversely correlates with immune-related signatures of ICI responsiveness. G9a inhibition restores interferon gamma (IFN-γ) signaling, increases major histocompatibility complex (MHC) class I expression, enhances CXCL10-mediated T cell recruitment, and induces viral mimicry via derepression of endogenous retroviral elements and cytosolic double-stranded RNA (dsRNA) accumulation. In vivo, G9a inhibition synergizes with anti-PD1 therapy, suppresses tumor growth, and enhances CD8+ T cell infiltration. These findings support combining G9a inhibitors with immunotherapy in HCC.