Immune checkpoint biology in hepatocellular carcinoma (Review).

Hepatocellular carcinoma (HCC) is a leading cause of cancer mortality worldwide, frequently arising in the setting of chronic liver inflammation and cirrhosis. Immune checkpoint inhibitors have transformed the treatment landscape for HCC, although response rates remain variable with only a subset of patients deriving durable benefit. The present review provides a comprehensive overview of immune checkpoint biology in HCC, examining their mechanisms of action and their roles within the tumor microenvironment. The present review discusses not only well-established checkpoints (programmed cell death-1 and cytotoxic T-lymphocyte antigen-4) but also emerging inhibitory targets (lymphocyte-activation gene 3, T-cell immunoglobulin and mucin-domain 3, T-cell immunoreceptor with Ig and immunoreceptor tyrosine-based inhibitory motif domains, B and T lymphocyte attenuator, V-domain immunoglobulin suppressor of T-cell activation, B7 homolog 3, B7 homolog 4 and CD47) increasingly recognized in HCC immunology. The clinical implications of checkpoint expression patterns are explored, including their prognostic significance and potential as predictive biomarkers. Current therapeutic strategies are reviewed, from monotherapy approaches to combination regimens involving dual checkpoint blockade and anti-angiogenic agents. Despite recent advances, significant challenges persist, including primary and acquired resistance, the immunosuppressive liver microenvironment and safety concerns in patients with underlying liver dysfunction. Future directions focusing on novel checkpoint targets, innovative combination approaches, personalized cellular therapies and biomarker-driven treatment selection offer potential avenues to improve outcomes for patients with HCC in the future.