Synergistic strategies of tumor ablation and immunotherapy in hepatocellular carcinoma: mechanisms, clinical translation, and perspectives
- 1Mini-invasive Interventional Therapy Center, Shanghai East Hospital, Tongji University
Abstract
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.
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BibTeX
@article{liu2026synergistic,
title = {{Synergistic strategies of tumor ablation and immunotherapy in hepatocellular carcinoma: mechanisms, clinical translation, and perspectives}},
author = {Ying Liu and Linke Bian and Hongye Wang and Dan Cui and Zhaorong Wu and Bo Zhai},
journal = {Holistic Integrative Oncology},
year = {2026},
month = oct,
doi = {10.1007/s44178-026-00303-7},
url = {https://doi.org/10.1007/s44178-026-00303-7},
note = {CC BY},
}
RIS
TY - JOUR
TI - Synergistic strategies of tumor ablation and immunotherapy in hepatocellular carcinoma: mechanisms, clinical translation, and perspectives
AU - Ying Liu
AU - Linke Bian
AU - Hongye Wang
AU - Dan Cui
AU - Zhaorong Wu
AU - Bo Zhai
PY - 2026
DA - 2026/10/25
JO - Holistic Integrative Oncology
DO - 10.1007/s44178-026-00303-7
UR - https://doi.org/10.1007/s44178-026-00303-7
AB - 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.
SN - 2731-4529
ER -