设计合成FR-β/PI3Kγ靶向嵌合分子调控TAM极化作用及抗肿瘤免疫机制研究

肿瘤相关巨噬细胞（TAM）是肿瘤免疫治疗的研究热点，多个候选药物处于临床试验阶段。缺乏对TAM的选择性是限制其研究和开发的关键问题。本项目的核心是探索促进TAM向抗肿瘤方向再极化分子设计中，M2型TAM选择性与极性转化作用的协同设计和机制研究。主要的研究思路是基于M2型TAM表面标志物FR-β受体和可诱导TAM发生M2型极化的PI3Kγ信号通路，设计兼顾靶向性和TAM再极化作用的嵌合分子。在前期研究基础和已有平台的支撑下，本项目拟通过药物化学方法设计并合成FR-β/PI3Kγ靶向嵌合分子，对其化学结构进行表征；综合运用生化与分子生物学、细胞生物学、动物模型等多种技术手段研究嵌合分子靶向进入M2型TAM，通过抑制PI3Kγ通路调控M2型TAM发生再极化，从而恢复抗肿瘤免疫作用；阐明嵌合分子与TAM极性转化的关系及可能机制，为靶向TAM的肿瘤免疫治疗提供新思路。

Tumor-associated macrophages (TAM) are hot research topics in tumor immunotherapy. Several drug candidates are under clinical trials. The lack of selectivity for TAM is a key issue limiting its research and development. The aim of this project is to explore the collaborative design and mechanism study in both M2/TAM selectivity and its repolarization to promote TAM antitumor immunity. The main research idea is to design chimeric molecules in both targeting M2/TAM and regulating its polarization, based on FR-β, a surface marker of M2/TAM and PI3Kγ signaling pathway, inducing TAM to undergo M2 polarization. Supported by our preliminary research results, it is intended to design and synthesize chimeric molecules targeting FR-β/PI3Kγ through medicinal chemistry methods and to characterize their chemical structures. It is also planned to apply biochemical and molecular biology, cell biology techniques and animal models to study targeted entry of chimeric molecules into M2/TAM, regulation of TAM polarization through inhibiting PI3Kγ signaling pathway, thereby restoring antitumor immunity. It is aimed to elucidate the relationship and the possible mechanism between FR-β/PI3Kγ based chimeric molecules and TAM polarization, which would provide new ideas for TAM-targeted tumor immunotherapy.