Current Status and Future Perspectives of Systemic Therapy for Advanced Hepatocellular Carcinoma: From Mechanistic Paradox to Precision Oncology

The therapeutic landscape for advanced HCC has expanded with ICI combinations, yet durable survival remains limited—an efficacy paradox from regimen proliferation without consistent long-term benefit, reflecting persistent biological constraints. We replace the trial-chronology approach with a mechanism-driven framework integrating the immunological basis of the HCC 'cold' microenvironment, liver immune tolerance and immune-privileged regulation, ICI–TKI-induced microenvironment remodeling, and how etiologic heterogeneity and dynamic resistance shape durability. This synthesis reveals three key limitations: First, low intrinsic immunogenicity and constrained de novo immune generation restrict sustained checkpoint blockade-induced anti-tumor immunity. Second, ICI–TKI synergy is target-mediated rather than serendipitous: TKIs remodel the microenvironment to create a time-limited window for ICI action, not merely potentiating pre-existing immunity. Third, the biomarker void and etiology-related differences prevent reliable patient matching, fostering an illusion of choice, while regimen-specific, evolving resistance complicates treatment sequencing and safety under liver-function constraints. Precision oncology for advanced HCC should therefore shift from regimen accumulation to implementation guidance: deploy multi-omic and dynamic biomarkers for patient stratification and risk-aware sequencing; target beyond PD-1/PD-L1 and VEGF axes to address oncogenic drivers and immune escape; and advance cure-oriented perioperative pathways with standardized definitions and evidence-based endpoints. Future work must focus on these three core directions: multi-omic biomarkers, novel therapeutic targets, and cure-oriented strategies.