PD1单抗是最具前景抗肿瘤药，但耐药突出。我们认为“热毒蕴结”是应用PD1单抗后的主要证候。前期在黑色素瘤模型中发现黄连解毒汤（HLJD）可增敏PD1单抗，同时增加肿瘤CD8+T细胞浸润，RNA-seq提示IFN-γ和ROS通路激活。据此提出假说：HLJD可改造黑色素瘤细胞（升高ROS，继而激活IFN-γ通路，增加下游CXCL10分泌），吸引更多T细胞浸润肿瘤，为PD1单抗增敏创造条件。本项目拟在UV3荷瘤鼠中明确HLJD增敏PD1单抗的最佳给药组合及剂量，分析其对免疫细胞分型及功能的影响，并检测肿瘤ROS/IFN-γ/CXCL10通路。此外还拟分别采用ROS清除剂、IFN-γ通路抑制剂、CXCL10中和抗体和CD8+T细胞清除抗体干预，观察HLJD的增敏可否被逆转。本项目从传统中药中寻找PD1单抗增敏剂，并从肿瘤细胞-T细胞交叉对话角度探讨增敏机制，有望为PD1单抗耐药逆转提供新选择。

Anti-PD1 is one of the most promising drugs for cancer therapy. Drug resistance is an urgent problem for anti-PD1, and the low response of IFN-γ signaling pathway is the main mechanism. The combination of Chinese and western medicine is a feature of tumor prevention and treatment in China, and many patients will use both traditional Chinese medicine and anti-PD1.Can Chinese medicine sensitize anti-PD1? What is the mechanism? Our previous study found that huanglian jiedu tang (HLJD) can sensitize anti-PD1, and RNA-seq suggested that it can activate IFN-γ and ROS pathways. Given that ROS can activate the IFN-γ pathway, we speculate that HLJD can transform melanoma cells (increase ROS, then activating the IFN-γ pathway, increase CXCL10 secretion) to attract more CD8+T cells, create conditions for the sensitization of anti-PD1.In addition to the ROS/ IFN-γ /CXCL10 pathway, this project intends to use ROS scavenger, IFN-γ pathway inhibitor, CXCL10 neutralizing antibody and CD8+T cell scavenger antibody respectively to observe whether the sensitization of HLJD can be reversed.This project seeks for the sensitizers of anti-PD1 from traditional Chinese medicine and explores the mechanism from the perspective of tumor-T cell cross-talk, which is expected to provide a new option for the reversal of anti-PD1 resistance.