褪黑素联合PD-L1单抗治疗肝癌射频消融后残存和远处转移瘤的疗效及机制研究

射频消融（RFA）是当前肝癌治疗的重要手段之一，但术后肿瘤复发和转移仍是困扰临床医生的一大难题。前期研究及我们预实验表明，RFA术后残存肿瘤内部缺氧微环境能加剧其侵袭和转移能力。同时申请人的临床研究显示，和完全消融相比，不全消融患者生存时间及肿瘤新发转移时间更短。因此，改善残存肿瘤内部缺氧微环境至关重要。近期研究发现：褪黑素可有效抑制缺氧诱导因子的表达，还能抑制肿瘤血管新生及转移。前期实验结果显示褪黑素能显著改善不全消融后残存肿瘤内部缺氧微环境，但PD-1+CD8T细胞无法有效杀伤肿瘤细胞。当前临床上应用的PD-L1单抗能阻断肿瘤细胞表面抗原PD-L1与CD8T细胞表面PD-1结合，防止肿瘤免疫逃逸。基于此，本研究拟采用褪黑素联合PD-L1单抗治疗肝癌RFA后残存和远处转移瘤，在改善残存肿瘤内部缺氧的同时还可增强CD8T细胞的肿瘤杀伤能力。本项目将为肝癌综合介入治疗提供理论依据和实践基础。

Radiofrequency ablation (RFA) is one of the most important methods for the treatment of hepatocellular carcinoma, but postoperative tumor recurrence and metastasis are still a major problem for clinicians. Previous studies and our preliminary experiments have shown that hypoxic microenvironment in residual tumors after RFA can aggravate tumor invasion and metastasis. Meanwhile, the applicant's clinical study indicated that compared with complete ablation, patients with incomplete ablation had shorter survival time and less time to develop new metastases. Therefore, it is very important to improve the hypoxic microenvironment in the residual tumor. Recent studies have found that melatonin can effectively inhibit the expression of hypoxia-inducible factor-1α, and also inhibit tumor angiogenesis and metastasis. However, preliminary experimental results demonstrated that although melatonin could significantly improve the hypoxic microenvironment in the residual tumor after incomplete ablation, PD-1+CD8+T cells could not play an effective killing effect on residual tumor cells. Immune checkpoint inhibitor anti-PD-L1 monoclonal antibody can block the binding of tumor cell surface antigen PD-L1 and CD8+T cell surface receptor PD-1 to prevent tumor immune escape. Therefore, this study intends to use melatonin combined with anti-PD-L1 monoclonal antibody in the treatment of residual and distant metastatic tumors after RFA, which can not only improve the hypoxia of residual tumors, but also enhance the tumor killing ability of CD8+T cells. This project will provide theoretical basis and practical basis for the comprehensive interventional therapy of hepatocellular carcinoma.