Harnessing Immune Microenvironment Reprogramming in Hepatocellular Carcinoma: Mechanisms and Therapeutic Innovation

Hepatocellular carcinoma (HCC) remains a lethal malignancy with limited therapeutic options due to immune evasion and resistance to immune checkpoint inhibitors (ICIs). The tumor microenvironment (TME) is characterized by immune suppression driven by macrophage polarization (e.g., M2-like TAMs), epigenetic dysregulation (e.g., m6A methylation enhancing PD-L1 expression), and metabolic crosstalk (e.g., lactate/lipid-mediated immunosuppression). These interconnected mechanisms create multi-layered barriers to effective immunotherapy. While synthetic drugs face toxicity and low efficacy, natural compounds offer unique immunomodulatory properties, such as macrophage repolarization and metabolic reprogramming, yet their mechanistic synergy with epigenetic/metabolic pathways remains unexplored.

This Research Topic aims to unravel the synergistic mechanisms driving immune evasion in hepatocellular carcinoma (HCC) by integrating three interconnected dimensions: m6A-mediated T cell exhaustion, macrophage-driven metabolic suppression, and natural compound-driven immunoregulation. We aim to overcome resistance to immune checkpoint inhibitors (ICIs) and develop a precision immunotherapy framework for HCC, addressing unmet clinical needs and advancing biomaterial-based treatment strategies.

Specifically, submissions that address the following themes are highly welcome:
● Macrophage Polarization and Functional Reprogramming: Investigate dynamic mechanisms of TAMs polarization (e.g., M2-like phenotypes) and their crosstalk with metabolic/epigenetic pathways (e.g., m6A-modulated PD-L1 expression). Both in vitro/in vivo validation of macrophage-driven immunosuppression are required.
● m6A-Mediated T Cell Exhaustion: Explore how m6A modifications regulate PD-L1 mRNA stability and T cell dysfunction in HCC. Studies should include clinical sample validation (e.g., TCGA/ICGC cohorts) or functional assays (e.g., CRISPR editing of METTL3).
● Metabolic-Immune Crosstalk: Define roles of tumor-derived metabolites (lactate/lipids) in dendritic cell suppression and Treg expansion. Experimental validation (e.g., metabolite depletion assays) and therapeutic targeting strategies are required.
● Natural Compounds-Driven Immunomodulation: Evaluate multi-targeting effects of natural products (e.g., curcumin, resveratrol) on TME reprogramming. Mechanistic studies (e.g., network pharmacology + RNA-seq) and preclinical efficacy assessment (e.g., syngeneic models) are required.
● Therapeutic Strategies: Develop combinatorial approaches (e.g., m6A inhibitors + macrophage repolarizers) with validation in patient-derived organoids or clinical trial readiness.


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

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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
• Study Protocol
• Systematic Review
• Technology and Code

Keywords: hepatocellular carcinoma immune microenvironment reprogramming, m6A methylation-mediated T cell exhaustion, Lactic acid/lipid metabolic crosstalk, macrophage polarization and functional reprogramming, natural compounds-driven 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.