Epigenetic and Epitranscriptomic Regulation of Immune Checkpoint Response in Hepatocellular Carcinoma: Mechanisms, Therapeutic Targeting, and Translational Challenges.

Abstract

Immune checkpoint inhibitors (ICIs) have reshaped systemic therapy for hepatocellular carcinoma (HCC), but durable benefit remains limited to a subset of patients because of tumor-intrinsic and microenvironmental mechanisms of immune resistance. Canonical epigenetic and epitranscriptomic alterations, including DNA methylation, histone modifications and chromatin remodeling, and epitranscriptomic RNA modifications, can influence tumor immune visibility by regulating antigen presentation, interferon responses, chemokine production, T-cell recruitment and function, and immunosuppressive programs in myeloid and stromal cells. This review critically evaluates HCC-specific evidence linking these regulatory mechanisms to immune checkpoint responsiveness. Emphasis is placed on crosstalk among DNA methylation, histone/chromatin regulation, and N6-methyladenosine (m6A)-dependent pathways; transcriptional-epigenetic stabilization of T-cell dysfunction; and epigenetic or epitranscriptomic remodeling of myeloid and stromal compartments, including cancer-associated fibroblasts. We further evaluate candidate therapeutic targets using a tiered evidence framework that integrates molecular association, mechanistic validation, pharmacologic validation, evidence from ICI-combination studies, and clinical validation. We assess therapeutic targets by evidence maturity and discuss emerging combination strategies and HCC-specific translational challenges, including chronic liver disease, limited hepatic reserve, and biomarker-guided patient selection. Although preclinical studies support several candidate mechanisms for modulating ICI responsiveness, mature clinical evidence for epigenetic-ICI combinations in HCC remains limited. These strategies should therefore be regarded as mechanistically compelling but clinically unproven and require rigorously designed, biomarker-integrated HCC trials with pharmacodynamic confirmation of immune reprogramming and careful safety evaluation.