Enhancing Radiofrequency Ablation for Hepatocellular Carcinoma: Nano‐Epidrug Effects on Immune Modulation and Antigenicity Restoration

Abstract Radiofrequency ablation (RFA), a critical therapy for hepatocellular carcinoma (HCC), carries a significant risk of recurrence and metastasis, particularly owing to mechanisms involving immune evasion and antigen downregulation via epigenetic modifications. This study introduces a “nano‐epidrug” named MFMP. MFMP, which is composed of hollow mesoporous manganese dioxide (MnO₂) nanoparticles, FIDAS‐5 as an MAT2A inhibitor, macrophage membrane, and anti‐PD‐L1 (aPD‐L1), targets HCC cells. By selectively binding to these cells, MFMP initially reverses immune suppression via PD‐L1 inhibition. After endocytosis, MFMP disassembles in the tumor microenvironment, releasing FIDAS‐5 and Mn²⁺. FIDAS‐5 prevents cGAS methylation, whereas Mn²⁺ aids STING pathway restoration. In addition, FIDAS‐5 reduces m⁶A RNA modification, suppressing EGFR expression. These changes enhance HCC antigenicity to promote cytotoxic T cell recognition and cytotoxic killing. Furthermore, MFMP mediates immunogenic cell death in HCC by synergizing with RFA through cGAS DNA demethylation, EGFR mRNA demethylation, and TBK1 protein phosphorylation, thereby inhibiting recurrence and metastasis and enhancing immune memory. Thus, MFMP is a potential adjunctive therapy requiring clinical validation.