肿瘤的免疫逃逸是其得以恶性增殖的重要原因之一。免疫检测点阻断是防止肿瘤免疫逃逸的重要策略，也是肿瘤免疫治疗的有效手段。免疫检测点PD-1/PD-L1信号轴在肿瘤免疫逃逸中发挥重要作用，其抗体药物已被批准应用于临床，但相应的小分子药物研究仍处于起步阶段。我们前期研究中发现，源自抗肿瘤中草药元宝草的一类多环多异戊烯基取代间苯三酚类化合物（PPAPs）可通过结合PD-L1阻断PD-1/PD-L1信号轴功能，在体内外表现出明确的抗肿瘤活性。本项目拟在此基础上，结合分离提取、结构优化以及理性设计等方式构建该类天然产物及其衍生物库；通过评价筛选发现低毒高效的新活性分子；研究其与PD-L1之间的相互作用规律，并阐述其构效关系；在细胞与模式动物水平探索其对T淋巴细胞的激活作用以及对相关信号通路的影响；并在体内外研究其抗肿瘤活性，为靶向PD-1/PD-L1信号轴的创新小分子免疫抑制药物研发提供坚实的基础。

Immune escape is one of the most important reasons for the malignant proliferation of tumor. Immune checkpoint blockade is an effective strategy to prevent tumor immune escape, and is also an effective means for tumor immunotherapy. The immune checkpoint PD-1/PD-L1 signal axis plays an important role in tumor immune escape, and its antibody drugs have been approved for clinical application. However, the study of small molecule drugs targeting PD-1/PD-L1 signal axis is still in the early stage. In our previous studies, a class of polycyclic polyprenylated acylphloroglucinols (PPAPs) from Chinese herbs Hypericum sampsonii Hance interfered with the interaction between PD-1 and PD-L1 by targeting PD-L1, and showed good antitumor activity in vitro and in vivo. Based on these previous findings, this project will establish natural PPAPs and their derivatives library by combining with separation/extraction, structural optimization, and rational design; screen and discovery new active molecules with low toxicity and high efficiency; study the interaction between them and PD-L1, and discuss their structure-activity relationship; explore the effects and mechanisms of compounds on the activation of T lymphocyte and related signaling pathways in cells and animal models; evaluates their antitumor activity in vivo and in vitro. These studies will afford a solid foundation for the development of small molecule immunosuppressive drugs targeting the PD-1/PD-L1 signal axis.