射频消融（iRFA）不足引起的残留肿瘤的缺氧微环境和炎症状态是肿瘤快速进展的主要原因，也给免疫治疗带来了挑战。我们回顾性分析了接受 RFA 治疗的肝细胞癌 (HCC) 患者的临床数据，发现 iRFA 与不良生存结果和无进展生存相关。使用原位 HCC 小鼠模型和结直肠肝转移模型，我们观察到 iRFA 后使用褪黑激素治疗可减少肿瘤生长和转移，并在与抗程序性死亡配体 1（抗 PD-L1）治疗相结合时取得最佳结果。机制上，褪黑素抑制 iRFA 后肿瘤细胞中上皮间质转化、缺氧诱导因子 (HIF)-1α 和 PD-L1 的表达。流式细胞术显示，褪黑激素降低了骨髓源性抑制细胞的比例，增加了 CD8 T 细胞的比例。转录组分析显示残留肿瘤中免疫激活功能相关基因的上调。这些发现表明，褪黑激素可以逆转缺氧和 iRFA 诱导的炎症，从而克服免疫抑制性肿瘤微环境 (TME)，增强免疫治疗的疗效。© 2024 作者。

The hypoxic microenvironment and inflammatory state of residual tumors caused by insufficient radiofrequency ablation (iRFA) are major reasons for rapid tumor progression and pose challenges for immunotherapy. We retrospectively analyzed the clinical data of patients with hepatocellular carcinoma (HCC) treated with RFA and observed that iRFA was associated with poor survival outcomes and progression-free survival. Using an orthotopic HCC mouse model and a colorectal liver metastasis model, we observed that treatment with melatonin after iRFA reduced tumor growth and metastasis and achieved the best outcomes when combined with anti-programmed death-ligand 1 (anti-PD-L1) therapy. In mechanism, melatonin inhibited the expression of epithelial-mesenchymal transitions, hypoxia-inducible factor (HIF)-1α, and PD-L1 in tumor cells after iRFA. Flow cytometry revealed that melatonin reduced the proportion of myeloid-derived suppressor cells and increased the proportion of CD8+ T cells. Transcriptomic analysis revealed an upregulation of immune-activated function-related genes in residual tumors. These findings demonstrated that melatonin can reverse hypoxia and iRFA-induced inflammation, thereby overcoming the immunosuppressive tumor microenvironment (TME) and enhancing the efficacy of immunotherapy.© 2024 The Author(s).