三阴性乳腺癌干性强，是乳腺癌中预后最差的类型。TNBC异质性高且发病分子机制不明，没有明确有效的治疗靶点。近期临床试验表明免疫检查点抑制剂治疗晚期PD-L1阳性TNBC获得较好的疗效，但是仅仅少数病人获益，具体原因不明。我们预实验结果表明PD-L1与TNBC细胞的恶性表型密切相关，特别是可以调节细胞的自发性凋亡，并首次发现PD-L1显著影响HIPPO/YAP干细胞通路，推测PD-L1可能是TNBC微环境免疫逃逸与干性维持的连接点，既促使肿瘤干细胞免疫逃逸，又维持微环境中CSC干性，PD-L1功能双重性可能与TNBC的ICI治疗耐受有关。本项目将深入研究PD-L1调控TNBC的HIPPO/YAP干细胞通路的分子机制，利用动物模型探讨ICI联合靶向HIPPO/YAP通路治疗的转化医学意义，将阐明目前肿瘤ICI治疗中所面临的共性难题，特备是TNBC，将奠定大幅提高ICI疗效的创新性理论基础。

Triple-negative breast cancer has basal-like features along with much more stemness and aggressiveness, and is the most severe type of breast cancer with the worst prognosis. TNBC has high heterogeneity and unclear pathogenesis, so there is no clear and effective therapeutic target. Recent clinical trials have shown that immunocheckpoint inhibitors(ICI) have achieved better efficacy in the treatment of advanced PD-L1 positive TNBC, but only a small number of patients have benefited, and the specific reasons are unknown. Our initial preliminary experimental results show that the PD-L1 are closely associated with TNBC cells malignant phenotype, and in particular, can adjust the spontaneous apoptosis of the cells. Via high-throughput RNA-Seq technology screening and KEGG pathway enrichment analysis, for the first time we found that PD-L1 significantly affect the HIPPO/YAP pathway, suggesting that the PD-L1 may be TNBC microenvironment immune escape and stemness maintenance connection point: on the one hand, on tumor stem cells to escape immune surveillance and strike, on the other hand, maintain CSC stemness in the microenvironment. The duality of PD-L1 function may be related to the limited effectiveness of ICI treatment of TNBC. This project will further investigate the in detail molecular mechanisms of PD-L1-mediated transcriptional activation of HIPPO/YAP pathways in TNBC stem cells. The translational medicine significance of ICI combined targeted HIPPO/YAP pathway therapy for TNBC was evaluated in animal models. This project will clarify the common problems faced by ICI in the treatment of tumors, especially TNBC, which is of significant pioneering and guiding significance, and will lay an innovative theoretical foundation for greatly improving the efficacy of ICI.