Progress in Research on the Mechanism of PD-1/PD-L1 Inhibitors in Down-Stage Conversion Therapy of Unresectable Liver Cancer

中国大多数原发性肝癌患者初诊时已是中晚期，失去了手术治疗的机会。针对不可切除肝细胞癌(Hepatocellular carcinoma, HCC)患者，局部介入治疗(如经动脉化疗栓塞术)和/或系统治疗(靶向药物、免疫治疗)可使肿瘤降期，从而使患者获得潜在手术干预机会及长期生存可能。近年来，肿瘤免疫微环境的动态调控机制逐渐被揭示，以免疫检查点抑制剂为代表的免疫治疗策略推动HCC治疗范式发生革命性突破。转化治疗对于大多数HCC患者而言，PD-1/PD-L1通路并不是抗肿瘤免疫的唯一限速因素。因此，联合治疗可能是更好的选择。本文解释了转化治疗的内涵，回顾了HCC患者免疫微环境的变化，对PD-1/PD-L1抑制剂的作用机制以及PD-1/PD-L1抑制剂联合用药作用机制进行总结，并列举联合治疗的案例及临床试验。Most patients with primary liver cancer in China are in the advanced stages when they are first diagnosed and have lost the opportunity for surgical treatment. For patients with unresectable hepatocellular carcinoma (HCC), local interventional therapy (such as transarterial chemoembolization) and/or systemic therapy (targeted drugs, immunotherapy) can reduce the tumor, thereby giving patients potential surgical intervention opportunities and long-term survival possibilities. In recent years, the dynamic regulation mechanisms of the tumor immune microenvironment have been gradually revealed, and immunotherapy strategies represented by immune checkpoint inhibitors have promoted revolutionary breakthroughs in the HCC treatment paradigm. At present, immunotherapy based on the programmed cell death protein-1 (PD-1)/programmed cell death protein ligand-1 (PD-L1) axis has achieved unprecedented success in HCC, but it also faces huge challenges, and its low response rate still needs to be resolved. For most HCC patients, the PD-1/PD-L1 pathway is not the only rate-limiting factor in anti-tumor immunity in conversion therapy. Therefore, combination therapy may be a better option. This article explains the content of conversion therapy, reviews the changes in the immune microenvironment of HCC patients, summarizes the mechanism of action of PD-1/PD-L1 inhibitors and the mechanism of action of PD-1/PD-L1 inhibitors combination, and lists cases and clinical trials of combination therapy.