Gong Yi, Xiong Yajun, Gao Yuting, Song Xiaoyong, Gong Yanli, Wang Dan, Liu Zhihan, Yang Yanguang, Lu Junlan, Zou Isabelle Xinyue, Shi Xinli
Laboratory of Integrated Medicine Tumor Immunology, Shanxi University of Chinese Medicine, Taiyuan, China.
Department of Pathobiology and Immunology, Hebei University of Chinese Medicine, Shijiazhuang, China.
Front Immunol. 2025 Aug 22;16:1658042. doi: 10.3389/fimmu.2025.1658042. eCollection 2025.
Cisplatin (DDP) is a clinical first-line chemotherapy drug for hepatocellular carcinoma (HCC), but treatment is often ineffective due to drug resistance. Yes-associated protein 1 (YAP1) is a critical regulator/factor in HCC tumor progression. Our previous research showed that DDP promoted the expression of YAP1 in mice bearing H22 cell in situ liver tumors, which might be related to the poor therapeutic effect of DDP.
DDP could inhibit tumor growth and decrease tumor volume in DEN/TCPOBOP-induced HCC mice, increase the number of CD8 T cells in the tumor, reduce the proportion of PD-1CD8 T cells in the peripheral blood and spleen of mice, and reduce the immune exhaustion of the tumor microenvironment in HCC. Of note, that DDP treatment activated YAP1 expression in HCC cells. In addition, using a murine model of subcutaneous transplantation of HCC cells, it was found that the combined use of the YAP1 inhibitor, verteporfin, and DDP led to significant tumor regression. Inhibition of YAP1 reduced activation of the cGAS-STING pathway by DDP treatment. Furthermore, bioinformatics analysis revealed that YAP1 was positively correlated with cGAS and STING in HCC tissues. We further confirmed the correlation of YAP1 with cGAS-STING in HCC using two models: DEN/TCPOBOP induction of HCC in hepatocyte-specific Y knockout mice; and giving verteporfin treatment to mice with subcutaneously transplanted HCC tumors. Inhibiting the expression of YAP1 in HCC tissues can reduce the expression of cGAS-STING and enhance the therapeutic effect of cisplatin.
The combination of YAP1 inhibitor, verteporfin and DDP enhances anti-tumor immunity by regulating the interaction between YAP1 and cGAS-STING in the tumor microenvironment, providing new insights into a combined chemotherapy strategy for HCC.
顺铂（DDP）是肝细胞癌（HCC）的临床一线化疗药物，但由于耐药性，治疗往往无效。Yes相关蛋白1（YAP1）是HCC肿瘤进展的关键调节因子。我们之前的研究表明，DDP促进了原位肝肿瘤荷H22细胞小鼠中YAP1的表达，这可能与DDP的治疗效果不佳有关。
DDP可抑制DEN/TCPOBOP诱导的HCC小鼠肿瘤生长并减小肿瘤体积，增加肿瘤中CD8 T细胞数量，降低小鼠外周血和脾脏中PD-1⁺CD8 T细胞比例，并减轻HCC肿瘤微环境的免疫耗竭。值得注意的是，DDP处理激活了HCC细胞中YAP1的表达。此外，利用HCC细胞皮下移植小鼠模型发现，YAP1抑制剂维替泊芬与DDP联合使用可导致肿瘤显著消退。抑制YAP1可降低DDP处理对cGAS-STING通路的激活。此外，生物信息学分析显示，HCC组织中YAP1与cGAS和STING呈正相关。我们使用两种模型进一步证实了HCC中YAP1与cGAS-STING的相关性：在肝细胞特异性Y基因敲除小鼠中通过DEN/TCPOBOP诱导HCC；对皮下移植HCC肿瘤的小鼠给予维替泊芬治疗。抑制HCC组织中YAP1的表达可降低cGAS-STING的表达并增强顺铂的治疗效果。
YAP1抑制剂维替泊芬与DDP联合使用通过调节肿瘤微环境中YAP1与cGAS-STING之间的相互作用增强抗肿瘤免疫力，为HCC联合化疗策略提供了新的见解。
