hnRNPs介导miRNAs成熟及外泌体分选机制在胶质瘤抑制性免疫微环境形成中的作用

胶质瘤是中枢神经系统最常见的恶性肿瘤，免疫治疗前景广阔，但其抑制性免疫微环境中浸润的M2型肿瘤相关巨噬细胞（TAMs）是限制其疗效的重要因素。我们前期研究发现，靶向TAMs的胶质瘤外泌体中富集了miR-204-3p等大量促M2极化的miRNAs，而hnRNPs家族蛋白不仅在其外泌体分选过程中起关键作用，还能通过m6A依赖的方式促进其在胶质瘤细胞中的剪切成熟。据此我们提出了m6A相关蛋白hnRNPI介导的miR-204-3p成熟及hnRNPA2B1介导其外泌体分选促进TAMs向M2极化的免疫抑制性微环境形成新假说。本课题拟利用RNA-蛋白互作和m6A修饰研究策略，在体内外深度解析hnRNPs在胶质瘤外泌体miRNAs分选和成熟中的分子机制，进而针对合成和外排两个关键环节中的hnRNPs设计干预方案，共同阻断外泌体中促M2极化相关miRNAs信号，为改善现有胶质瘤免疫治疗策略提供新的理论依据。

Glioma is the most common and malignant tumor in the central nervous system. Although anti-tumor immunotherapy is promising, it is limited by the tumor-infiltrating M2-type tumor associated macrophages (TAMs) in the immunosuppressive tumor microenvironment. In our previous studies, we found miR-204-3p and other microRNAs which could induce macrophage M2 polarization were enriched in glioma-derived exosomes. In addition, hnRNPs family members play important roles in sorting of microRNAs to exosomes. Moreover, they can facilitate microRNA maturation in m6A-dependent manner. Based on the above, we hypothesized that hnRNPI-mediated miR-204-3p maturation and hnRNPA2B1-mediated sorting of miR-204-3p to glioma exosomes may induce TAMs M2 polarization, therefore promoting the formation of the immunosuppressive tumor microenvironment. By utilizing strategies focused on RNA-protein interaction and m6A modification, we intend to reveal the mechanisms under which hnRNPs mediate the maturation and sorting of microRNAs. Furthermore, by targeting the key hnRNPs in microRNA maturation and sorting, we intend to block the microRNAs which can induce M2 polarization. We hope we can provide more novel foundation to improve anti-glioma immunotherapy.