Kdm2a histone demethylase ablation restores anti-tumor immunogenicity in liver cancer.

BACKGROUND: Liver cancer remains a major global challenge, with limited benefit from immune checkpoint inhibitors due to strong immune evasion. Emerging evidence indicates that chromatin modifiers shape tumor immunogenicity, but their roles in liver cancer immunity are not fully understood. METHODS: We investigated the role of the histone demethylase KDM2A in liver cancer using genetic silencing in vitro and in vivo. We evaluated mitochondrial function, redox balance, genomic stability, and performed transcriptomic and epigenomic analyses to assess immune pathway changes and H3K36me2 distribution. Immune infiltration was analyzed in human liver tumors and syngeneic mouse models. RESULTS: KDM2A silencing caused mitochondrial dysfunction, redox imbalance, and DNA damage, leading to activation of innate and adaptive immune pathways. It also reshaped H3K36me2 deposition at loci regulating chemokine signaling, metabolism, and T-cell recruitment. In human liver tumors, high KDM2A expression correlated with poor differentiation, macrophage enrichment, and exclusion of CD8⁺ T cells, consistent with an immune-excluded phenotype. In syngeneic models, KDM2A loss increased intratumoral CD8⁺ T-cell infiltration. CONCLUSIONS: KDM2A acts as a key epigenetic regulator of mitochondrial function, genomic stability, and the tumor immune microenvironment in liver cancer. Targeting KDM2A may enhance tumor immunogenicity and improve responses to immunotherapy, representing a promising therapeutic strategy.