膜融合脂质体原位重塑肿瘤表面糖信号以增强自然杀伤细胞抗肿瘤活性的研究

肿瘤细胞表面糖苷的突变是导致肿瘤逃离自然杀伤细胞（Natural killer cells, NK细胞）抗肿瘤免疫应答的核心因素。重塑肿瘤细胞表面糖信号是恢复NK细胞抗肿瘤活性以清除肿瘤的理想策略。本项目旨在构建多功能性膜融合脂质体（Membrane-fusogenic liposomes, MFL），利用其与肿瘤细胞的膜融合作用，同时实现对肿瘤表面糖苷的直接修饰和肿瘤内部糖信号合成通路的间接编辑，从而多途径协同地重塑肿瘤表面糖信号，以恢复NK细胞对肿瘤的免疫识别与杀伤作用来清除肿瘤。此外，为了优化MFL重塑肿瘤表面糖信号的效果，本项目拟构建含草酸酯的肿瘤微环境响应性可注射水凝胶，通过MFL在肿瘤部位的长效控制释放，以提高MFL对肿瘤表面糖信号改造的选择性。本项目的成功实施将为细胞表面的多功能模块化修饰开发新策略，为个性化调控细胞间相互作用探索出新方法，为肿瘤免疫治疗提供新的思路。

The mutation of glycosides on the tumor cell surfaces is the core factor that enables tumors to escape from anti-tumor immune responses of natural killer cells (NK cells). Remodeling the sugar signals on tumor surfaces is an ideal strategy to restore the anti-tumor activity of NK cells for tumor elimination. This project aims to construct a multi-functional membrane-fusogenic liposome (MFL) that can simultaneously achieve the direct modification of the tumor surface glycosides and indirect interference of sugar synthetic pathways by fusing with tumor cells, thereby multipath-synergistically reshaping the tumor surface sugar signals to restore the immune recognition and killing of NK cells to clear the tumor. In addition, to optimize the effect of MFL in remodeling tumor surface sugar signals, this project will construct an oxalate-based tumor microenvironment-responsive injectable hydrogel to enhance the selectivity of MFL through the long-term controlled release of MFL at the tumor site. The successful implementation of this project will develop new strategies for multifunction-modular modification of cell surfaces, explore new methods for personalized regulation of cell-cell interactions, and provide new ideas for tumor immunotherapy.