Evolving Landscape of Systemic Therapy for Hepatocellular Carcinoma: From Targeted Therapy and Combination Strategies to Emerging Therapies

Background: Hepatocellular carcinoma (HCC) is the predominant histological subtype of primary liver cancer, and many patients with unresectable disease require systemic therapy. This narrative review asks how current systemic regimens should be selected and sequenced, how oncogenic pathways inform resistance and biomarker development, and which emerging platforms have sufficient evidence for clinical translation. Methods: We synthesized key oncogenic pathways, pivotal trials, major guidelines, and selected translational studies cited in this review. Randomized phase III evidence was prioritized for clinical claims, whereas observational, early-phase, and preclinical studies were used to define evidence gaps and emerging approaches. Results: Immune-based combinations have reshaped first-line treatment for advanced HCC. Treatment selection must account for liver function, performance status, bleeding risk, and contraindications to anti-VEGF or immune checkpoint therapy. Evidence for post-immunotherapy sequencing remains largely observational, and validated predictive biomarkers are scarce. Conclusions: Future progress requires prospective sequencing studies, biomarker-enriched trials, and rigorous early-phase evaluation of cell, antibody, gene-editing, viral, and nanodelivery platforms.