Emerging Immune‐Based Therapeutic Strategies in Hepatocellular Carcinoma

ABSTRACT

Hepatocellular carcinoma (HCC) remains a leading cause of cancer‐related mortality worldwide despite recent advances in systemic therapy. The introduction of immune checkpoint inhibitors has substantially expanded treatment options for advanced disease; however, durable responses are observed only in a subset of patients. Increasing evidence indicates that this limited efficacy is largely driven by the complex immune landscape of HCC, which is shaped by disease aetiology, tumour microenvironment–mediated immune suppression, and impaired innate immune surveillance. Chronic viral hepatitis and metabolically driven liver diseases represent the principal drivers of HCC and profoundly influence immune regulation within the liver. Persistent antigen exposure, metabolic reprogramming, and stromal remodelling contribute to dysfunctional T‐ and natural killer (NK) cell responses, while immunosuppressive components of the tumour microenvironment, including tumour‐associated macrophages, myeloid‐derived suppressor cells, regulatory T cells, and inhibitory ligands such as HLA‐G, facilitate immune escape and therapeutic resistance. In this review, we discuss recent advances in HCC immunotherapy, focusing on emerging checkpoint pathways such as TIGIT and Tim‐3, glypican‐3 targeted cellular therapies and bispecific antibodies, and NK cell‐based therapeutic strategies. We further highlight the role of liquid biopsy approaches for treatment monitoring and biomarker development. Together, these insights emphasize the need for biomarker‐guided patient stratification and integrated therapeutic strategies to improve the clinical efficacy of immunotherapy in HCC.