以PD-1/PD-L1为靶标的免疫检查点阻断疗法(ICB)将成为三阴性乳腺癌临床治疗的重要突破方向，如何解除肿瘤微环境对T细胞的抑制效应从而提高患者的应答响应率是目前亟待解决的关键科学问题。M2表型极化的肿瘤相关巨噬细胞(TAMs)是浸润在肿瘤组织中最多的免疫细胞，在多个环节负性调控T细胞介导的抗肿瘤免疫应答。采用siRNA特异性阻断TAMs的STAT3信号传导通路及下游相关基因的表达，可为重塑TAMs的极化表型及免疫功能提供一条有效途径。然而稳定性差、清除率高、膜渗透性低的体内行为限制了基因药物在临床上的广泛应用。为此本项目拟构建金属配位驱动的仿生型肽基纳米自组装化递送系统，实现对siRNA的高效装载和pH/氧化还原双重环境响应释放，通过免疫重塑TAMs逆转肿瘤微环境介导的免疫抑制效应，其载体构筑模式及作用机制国内外未见报道，研究成果对于提高ICB的临床治疗效果具有重大的理论和实践意义。

Immunological checkpoint blocking therapy targeting PD-1/PD-L1 will become an important breakthrough in the clinical treatment of triple-negative breast cancer. How to relieve the inhibitory effect of tumor microenvironment on T cells and improve the response rate of patients is a key scientific issue that need to be addressed urgently. Tumor-associated macrophages (TAMs) with the M2-type polarized phenotype are the most infiltrating immune cells in tumor tissues, and negatively regulate T cell-mediated anti-tumor immune responses in multiple segments. The specific blocking of STAT3 signaling pathway and the expression of downstream related genes in TAMs by siRNA can provide an effective way to remodel the polarization phenotype and immunoregulatory function of TAMs. However, in vivo behavior with poor stability, high clearance and low membrane permeability limits the widespread clinical application of gene drugs. To this end, the project aims to construct a biomimetic peptide- based nano self-assembly delivery system driven by metal coordination, which can achieve efficient loading of siRNA and pH/redox dual environmental response release and reverse the immunosuppressive effect mediated by tumor microenvironment through immune remodeling of TAMs. The carrier construction model and mechanism of action have not been reported at home and abroad, and the research results have great theoretical and practical significance for improving the effectiveness of ICB treatment.