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.

中文翻译：

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增强肝细胞癌的射频消融术：纳米表皮药物对免疫调节和抗原恢复的影响


射频消融术 （RFA） 是肝细胞癌 （HCC） 的关键疗法，具有显著的复发和转移风险，特别是由于涉及免疫逃避和通过表观遗传修饰下调抗原的机制。本研究介绍了一种名为 MFMP 的“纳米表皮药物”。MFMP 由空心介孔二氧化锰 （MnO2） 纳米颗粒、FIDAS-5 作为 MAT2A 抑制剂、巨噬细胞膜和抗 PD-L1 （aPD-L1） 组成，靶向 HCC 细胞。通过选择性地结合这些细胞，MFMP 最初通过 PD-L1 抑制逆转免疫抑制。内吞作用后，MFMP 在肿瘤微环境中分解，释放 FIDAS-5 和 Mn2+。FIDAS-5 阻止 cGAS 甲基化，而 Mn2+ 有助于 STING 通路恢复。此外，FIDAS-5 可减少 m6A RNA 修饰，抑制 EGFR 表达。这些变化增强了 HCC 抗原性，以促进细胞毒性 T 细胞识别和细胞毒性杀伤。此外，MFMP 通过 cGAS DNA 去甲基化、EGFR mRNA 去甲基化和 TBK1 蛋白磷酸化与 RFA 协同作用，介导 HCC 中的免疫原性细胞死亡，从而抑制复发和转移并增强免疫记忆。因此，MFMP 是一种需要临床验证的潜在辅助疗法。