肿瘤细胞通过多种途径重塑组织微环境，建立有利于肿瘤生长和逃逸免疫监视的肿瘤微环境（TME）。外泌体是肿瘤细胞与免疫细胞间相互联系的重要媒介。肝癌细胞(HCC) 如何通过外泌体途径影响TME中免疫细胞特征、重塑免疫微环境、诱导效应细胞免疫耗竭的具体作用和机制尚未阐述。我们目前已观察到，HCC外泌体能促进巨噬细胞向M2型极化，进而诱导T细胞耗竭，并发现外泌体miRNA在该过程中发挥重要作用。本研究拟在此基础上，利用细胞生物学、生物信息学和分子生物学等技术手段，全面分析HCC外泌体中的miRNA谱，利用体内外模型对差异miRNA进行研究，发现外泌体中介导M2极化-T细胞/NK细胞耗竭这一过程的关键分子极其相关的信号通路，深入阐述肝癌细胞塑造肝脏免疫微环境的新机制，特别是不同细胞亚群之间的交互作用机制，为肝癌的临床治疗提供新的理论和策略。

Tumor cells remodel microenvironment via several pathways to create the tumor microenvironment (TEM) that is beneficial to tumor growth and immune escape. Exosomes is one of the important media for the interaction between tumor cells and immune cells. Hepatocellular carcinoma (HCC)-derived exosomes contributed to the formation of tumor immune microenvironment, but the related mechanisms has not been fully elucidated. Previously we observed that HCC-derived exosomes promoted macrophage toward type M2 polarization, and these exosome educated-macrophages enhanced the expression of checkpoint molecules on T cells. Furthermore, we found exosomal miRNAs displayed important role during this process. Based on these above, cellular biological, bioinformatics and molecular biological methods will be used to analyze the profile of HCC-exosomal miRNAs, investigate the differential miRNAs by in vitro and in vivo models, finding the key functional miRNAs in HCC-derived exosomes that induced M2 polarization and then T cell or/and NK cell exhaustion. The study will clarify new mechanisms of HCC in remodeling immune microenviroment, especially the cross-talk between different leukocytes. Therefore, this study will provide a new theoretical basis and new target for immunotherapy of hepatocellular carcinoma.