Immunotherapy Optimization in Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality worldwide, driven by marked molecular and clinical heterogeneity and frequent diagnosis at intermediate or advanced stages. Immune checkpoint inhibitors (ICIs) have reshaped the systemic treatment landscape for HCC, yet durable benefit is achieved in only a subset of patients. These inconsistent responses are closely linked to an immunosuppressive tumor microenvironment, impaired T-cell trafficking and function, dysfunctional antigen presentation, and metabolic and stromal barriers that promote immune escape. In addition, underlying liver disease and cirrhosis create a unique immune context that complicates therapeutic efficacy and toxicity management.

A rapidly evolving strategy to broaden and deepen responses involves rational combinations that convert “immune-cold” tumors into “immune-inflamed” states. Locoregional therapies—including transarterial chemoembolization (TACE), transarterial radioembolization with yttrium-90 (Y90), stereotactic body radiotherapy (SBRT), and thermal ablation—may induce immunogenic cell death, enhance antigen release, and remodel intratumoral immunity and tumor microenvironment, offering strong biological rationale for synergy with ICIs. Parallel advances in single-cell and spatial profiling, immunometabolism, and circulating biomarkers can enable patient stratification and early resistance monitoring. Finally, perioperative factors—such as surgical stress, anesthetic and analgesic techniques, and perioperative inflammation control—may influence immune surveillance and should be considered when designing multimodal strategies, particularly for patients with resectable or transplant-eligible HCC.

This Research Topic aims to highlight advances in optimizing immunotherapy for hepatocellular carcinoma through mechanistic, translational, and clinical research. We seek contributions that clarify determinants of response and resistance to ICIs, develop robust biomarkers for patient selection and treatment monitoring, and evaluate rational combination strategies to improve efficacy and safety. A key focus is the integration of immunotherapy with locoregional modalities (e.g., Y90 radioembolization, SBRT, TACE, ablation) and the design of treatment sequences that maximize immune priming while preserving liver function. We also welcome studies addressing other treatment modalities, for example, perioperative immune modulation—how anaesthetic/analgesic strategies and perioperative management may interact with antitumor immunity and treatment outcomes in HCC.

We welcome submissions, including original research and review articles that address, but are not limited to, the following themes:

● Mechanisms of immunotherapy resistance and immune evasion in HCC (tumor-, stroma-, and liver disease–driven factors).
● Immune biomarkers for patient stratification, early response assessment, and toxicity risk prediction (tissue, blood, and imaging-derived biomarkers).
● Novel strategies combining ICIs with locoregional therapies, including Y90 radioembolization, SBRT, TACE, thermal ablation, and other liver-directed approaches, with emphasis on mechanistic rationale, sequencing, and endpoints.
● Translational studies leveraging single-cell, spatial transcriptomics, proteomics, or immunometabolic profiling to map treatment-induced immune remodeling.
● Clinical trials and real-world studies evaluating combination regimens, timing/sequencing, liver function–guided personalization, and safety management.
● Perioperative immunomodulation in resectable HCC, including the potential influence of anaesthetic and analgesic techniques, perioperative inflammation control, and surgical stress on immune competence and recurrence risk.

Dr. Bo Liu is an employee of Eli Lilly and Company;
Dr. Jin-Ming Zhang is an employee of Minghui Pharmaceutical;
The remaining Topic Editors declare that they have no conflicts of interest.

Please note: Manuscripts consisting solely of bioinformatics, computational analysis, or predictions of public databases which are not accompanied by validation (independent clinical or patient cohort, or biological validation in vitro or in vivo, which are not based on public databases) are not suitable for publication in this journal.

Article types and fees

This Research Topic accepts the following article types, unless otherwise specified in the Research Topic description:

• Brief Research Report
• Case Report
• Clinical Trial
• Editorial
• FAIR² Data
• FAIR² DATA Direct Submission
• General Commentary
• Hypothesis and Theory
• Methods
• ... View all formats

Articles that are accepted for publication by our external editors following rigorous peer review incur a publishing fee charged to Authors, institutions, or funders.

Article types

This Research Topic accepts the following article types, unless otherwise specified in the Research Topic description:

• Brief Research Report
• Case Report
• Clinical Trial
• Editorial
• FAIR² Data
• FAIR² DATA Direct Submission
• General Commentary
• Hypothesis and Theory
• Methods
• Mini Review
• Opinion
• Original Research
• Perspective
• Review
• Systematic Review
• Technology and Code

Keywords: Hepatocellular carcinoma; Immunotherapy; Tumor microenvironment; Locoregional therapy; Biomarkers; Perioperative immunomodulation

Important note: All contributions to this Research Topic must be within the scope of the section and journal to which they are submitted, as defined in their mission statements. Frontiers reserves the right to guide an out-of-scope manuscript to a more suitable section or journal at any stage of peer review.