Ren Yanqiao, Zhu Licheng, Guo Yusheng, Ma Jinqiang, Yang Lian, Zheng Chuansheng, Dong Xiangjun
Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
J Pharm Anal. 2024 Aug;14(8):100942. doi: 10.1016/j.jpha.2024.01.010. Epub 2024 Feb 2.
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.
射频消融不足（iRFA）导致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与不良生存结局和无进展生存期相关。使用原位HCC小鼠模型和结直肠癌肝转移模型，我们观察到iRFA后用褪黑素治疗可减少肿瘤生长和转移，并且与抗程序性死亡配体1（抗PD-L1）疗法联合使用时效果最佳。在机制上，褪黑素抑制了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，褪黑素降低了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上调。这些发现表明，褪黑素可以逆转缺氧和iRFA诱导的炎症，从而克服免疫抑制性肿瘤微环境（TME）并增强免疫治疗的疗效。
