靶向重塑肿瘤相关巨噬细胞功能的纳米组装体及其对肿瘤免疫治疗的影响与机制研究

肿瘤相关巨噬细胞（TAMs）在肿瘤生长、转移、耐药性形成中具有重要作用。对其功能进行靶向重塑是肿瘤微环境调控的重要内容及研究难点。由于TAMs极化行为的多变性，有效的调控策略仍然缺乏。基于此，项目申请人拟在前期研究基础上，构建具有靶向TAMs功能的纳米组装体激活TLR促使TAMs向促炎表型极化，并抑制TAMs表达的免疫检查点PD-1活性，使TAMs表型功能得到实现，以此建立对肿瘤免疫治疗有促进作用的联合调控手段。同时，进一步考察不同表型巨噬细胞之间的生物学差异，优化极化调控体系，并考察该TAMs极化调控策略联合PD-L1阻断治疗对免疫微环境重塑过程中的作用及对肿瘤免疫治疗效果的影响，从而为肿瘤联合免疫治疗方案的构建提供指导。申请人团队前期的研究成果为本项目的实施提供了基础。本项目的顺利实施将为研究巨噬细胞极化调控对肿瘤免疫治疗的影响提供理论指导，并为肿瘤免疫治疗提供新策略。

Tumor associated macrophages (TAMs) play an important role in regulating tumor growth, metastasis and drug resistance. Targeted remodeling of its function is an important part of tumor microenvironment regulation. However, effective remodulation strategies still need to be further developed due to the variability of TAMs during polarization. Based on this, the applicant and his team intend to construct nanoassemblies with TAMs targeting function to promote the polarization of TAMs to pro-inflammatory phenotype via the activation of TLR, meanwhile, to inhibit the activity of PD-1, an immune checkpoint expressed by TAMs during tumor progression, so as to realize the phenotype function of TAMs, thus, establish a combinational regulatory strategy for TAMs regulation that can promote tumor immunotherapy. At the same time, we further investigate the biological differences between different phenotypes of macrophages, optimize the polarization regulation system, and evaluate the effect of TAMs polarization regulation strategy combined with PD-L1 blocking therapy on the process of immune microenvironment remodeling and the effect of tumor immunotherapy, therefore, provide guidance for the construction of tumor combinational immunotherapy. The preliminary research results of the applicant team provide the basis for the implementation of this project. The successful implementation of this project will provide theoretical guidance for studying the effect of macrophage polarization regulation on tumor immunotherapy, and provide new strategies for tumor immunotherapy.