Mechanisms of Resistance and Immune-Related Adverse Events Associated with Immune Checkpoint Inhibitors in Hepatocellular Carcinoma: A Narrative Review

Abstract

Abstract Immune checkpoint inhibitors (ICIs) have transformed the treatment of hepatocellular carcinoma (HCC), but their clinical benefits are constrained by primary and acquired resistance and immune-related adverse events (irAEs). Understanding the biological processes underlying these outcomes is essential for improving treatment efficacy and safety. This narrative review synthesizes evidence on ICI resistance and irAEs in HCC across tumor-intrinsic, microenvironmental, and systemic dimensions. Primary resistance involves impaired tumor antigen presentation, dysregulated oncogenic signaling, limited immune-cell infiltration, metabolic immunosuppression, and systemic immune dysfunction, with additional influences from the gut microbiota and underlying liver disease. Acquired resistance may involve immunoediting and clonal escape, compensatory inhibitory checkpoint signaling, and treatment-associated immunosuppressive remodeling of the tumor microenvironment. Mechanisms potentially contributing to irAEs include loss of peripheral immune tolerance, T-cell-mediated tissue injury, dysregulated inflammatory cytokine production, antigenic cross-reactivity, and autoantibody-associated immune dysregulation. The strength of evidence varies substantially across these mechanisms: several are supported by experimental HCC models and clinical observations, whereas others remain largely extrapolated from non-HCC settings or lack causal validation. Future priorities include integrating baseline and longitudinal tumor and host immune profiling to develop predictive biomarkers, detect emerging resistance, and identify patients at increased risk of severe toxicity. Prospective HCC-specific studies are needed to determine whether mechanism-guided interventions can improve outcomes. A more precise understanding of antitumor immunity and tissue tolerance may inform individualized strategies that sustain tumor control while preserving liver function and minimizing immune-related toxicity.