生物工程化微泡干扰MAPK通路重编程CNS微环境起始脑胶质瘤免疫检查点抑制剂的应答研究

血脑屏障的存在和胶质瘤的高度异质性、抑制性免疫微环境和高重塑性是脑胶质瘤免疫治疗响应率低的主要原因。巨噬细胞/小胶质细胞占胶质瘤浸润免疫细胞数量的50%以上，是改善肿瘤免疫微环境的重要靶标。浸润的巨噬细胞主要为促癌的M2型巨噬细胞，因此重编程巨噬细胞/小胶质细胞可有效改善肿瘤抑制微环境，但靶向重编程巨噬细胞/小胶质细胞药物的缺乏和血脑屏障阻碍了脑胶质瘤免疫微环境的改善。本课题前期通过抑制USP7去泛素化酶活性可有效调控MAPK信号通路，促进M2型巨噬细胞重编程，并且前期研究揭示肿瘤细胞放疗后微囊泡可作为天然药物载体靶向巨噬细胞，但无法有效穿透血脑屏障；基于此，本课题以基因编程手段使包裹USP7抑制剂的放疗后微泡膜表面表达转铁蛋白和SR-B1靶向性多肽R4F，促进微泡浸润大脑，靶向调控巨噬细胞/小胶质细胞的MAPK信号通路，增强PD-1抗体的免疫应答。该研究将为临床治疗脑胶质瘤患者提供新思路。

The existence of blood-brain barrier and the high heterogeneity, inhibitory immune microenvironment and high remodeling of glioma are the main reasons for the low response rate of glioma immunotherapy.Macrophages/microglia cells account for more than 50% of the number of infiltrated immune cells in glioma, and are important targets for improving the tumor immune microenvironment.The infiltrating macrophages are mainly M2-type macrophages that promote cancer. Therefore, reprogramming macrophages/microglias can effectively improve the tumor inhibition microenvironment. However, the lack of drugs targeting reprogramming macrophages/microglias and the blood-brain barrier hinders the improvement of the immune microenvironment of glioma.In the early stage of this study, MAPK signaling pathway can be effectively regulated by inhibiting USP7 deubiquitination enzyme activity to promote the reprogramming of M2-type macrophages. In addition, previous studies revealed that microvesicles of tumor cells after radiotherapy can be used as natural drug carriers to target macrophages, but they cannot effectively penetrate the blood-brain barrier.Based on this, this study used genetic programming to make the surface of the radiotherapy microvesicle coated with USP7 inhibitor express transferrin and SR-B1 targeting polypeptide R4F, promote the infiltration of microvesicle into the brain, regulate the MAPK signaling pathway of macrophages/microglia, and enhance the immune response of PD-1 antibody.This study will provide a new idea for the clinical treatment of patients with glioma.