Synergistic strategies of tumor ablation and immunotherapy in hepatocellular carcinoma: mechanisms, clinical translation, and perspectives

Hepatocellular carcinoma (HCC) remains the third leading cause of cancer-related mortality worldwide, accounting for over 85% of primary liver cancers. Locoregional ablation techniques—encompassing thermal modalities such as radiofrequency ablation (RFA) and microwave ablation (MWA), and non-thermal approaches including cryoablation (CA) and irreversible electroporation (IRE)—have been established as standard-of-care options for early-stage HCC. Ablation induces immunogenic cell death (ICD), releasing tumor-associated antigens (TAAs) and damage-associated molecular patterns (DAMPs) that prime antitumor immunity; however, this response is transient and insufficient to overcome the immunosuppressive tumor immune microenvironment (TIME), necessitating combination with immunotherapy. While preclinical evidence supports ablation-immunotherapy synergy across multiple platforms, robust phase III clinical data demonstrating survival benefit remain limited. This review systematically summarizes the immunological mechanisms underlying tumor ablation, and primarily discusses: (1) Modality-specific immune profiles—thermal ablation induces broad DAMP release but is limited by antigen denaturation and by incomplete ablation (iRFA), which associates with SUMO2-mediated IFN-I suppression, whereas non-thermal modalities (CA, IRE) preserve antigen conformation and engage multiple regulated cell death pathways; (2) Comprehensive combination strategies addressing three immunological barriers: innate APC licensing (PRR agonists, STING, GM-CSF, nanobiomaterials), T cell priming and trafficking (immune checkpoint inhibitors and adoptive cell therapy), and systemic memory durability (oncolytic viruses); (3) Critical mechanistic barriers to clinical translation: iRFA paradoxically couples residual tumor substrate with immunosuppression; the post-ablation immune activation window (3–14 days) remains clinically unexploited; and mechanistic understanding substantially outpaces clinical validation. Collectively, these advances support the continued development of personalized and precision-guided ablation–immunotherapy strategies for HCC.