Immunotherapy and Hepatocellular Carcinoma: From Tumor-Immune Cell Interactions to Rational Therapeutic Strategies

Hepatocellular carcinoma (HCC) remains one of the leading causes of cancer-related death worldwide, and first-line systemic treatment has shifted toward immune checkpoint inhibitor (ICI)-based combinations. Response is heterogeneous, and mechanistic interpretation has lagged behind clinical practice, leaving open the question of why some tumors respond while others do not. This review uses the cancer immunity cycle as an HCC-specific scaffold to map where anti-tumor immunity fails—across priming, trafficking, suppressive myeloid or stromal, and metabolic-hypoxic barriers—and interpret combination strategies and resistance through the dominant barrier each tumor presents. ICI monotherapy rescues only specific failure points within the cycle. Combination regimens may be more effective when they are matched to one or more dominant barriers, whereas response may fail when the selected partner addresses only a secondary barrier while the dominant ecological constraint remains intact. Resistance can be similarly organized into tumor cell autonomous, microenvironmental, treatment-induced, and etiology-specific layers, with disease etiology shaping both baseline immune ecology and therapy-context vulnerability. A mechanism-based, biomarker-guided, and etiology-aware framework may help move the field from broad empiricism toward precision immunotherapy, but it should be viewed as a conceptual and translational organizing model that requires prospective testing in biomarker-stratified studies.