M2型的肿瘤相关巨噬细胞（TAMs）促进肝细胞肝癌（HCC）的发生发展。IRE1α是内质网应激的关键感受器和效应分子，申请人前期研究发现肝癌细胞内IRE1α的过度激活可以促进肿瘤微环境中巨噬细胞浸润和M2型TAMs生成，但其具体调控机制不清。外泌体参与细胞间交流，申请人发现肝癌细胞分泌的外泌体可以促进M2型TAMs形成，而IRE1α敲除的肝癌细胞则失去了这一功能。基于此，本项目拟利用不同肝癌细胞系和肝细胞特异性敲除IRE1α的小鼠，借助基因芯片、生物信息学分析及外泌体转染干扰等技术，进一步证实肝癌细胞中IRE1α参与调控微环境巨噬细胞的浸润并通过外泌体调控TAMs的表型转化，进而促进肝癌发生发展，揭示参与这一调控过程中的外泌体内重要信息分子（如miRNA等），并明确其分子机制。研究结果为阐明肝癌的病理学基础提供新的视角，更有可能为肝癌的新型免疫治疗策略提供理论依据。

Tumor-associated macrophages (TAMs) of the M2 phenotype promote the progression of hepatocellular carcinoma (HCC). The endoplasmic reticulum (ER)-localized transmembrane protein inositol-requiring enzyme 1α (IRE1α) mediates a key signaling branch of the unfolded protein response (UPR). Our previous study revealed the critical role for IRE1α in regulating the infiltration and activation of TAMs in HCC progression, but the underlying molecular mechanism is still unclear. As important carries of intercellular information, exosomes are implicated in the crosstalk between HCC cells and TAMs. Our preliminary study demonstrates that the abrogation of IRE1α efficiently impairs the capacity of tumor cells in activating TAMs into the M2 phenotype via secreting exosomes. In our current project, we will utilize HCC cell lines and liver-specific IRE1α knockout mice in combination with bioinformatics and exosomes transfection-associated techniques to illustrate the molecular mechanism underlying IRE1α-mediated TAMs activation and tumor microenvironment in HCC. This study will provide a new insight into the pathology and immunotherapy strategies for HCC.