肿瘤微环境的免疫抑制状态是影响肝癌药物治疗疗效的关键因素。我们前期结果表明肝癌细胞低表达富组氨酸糖蛋白（HRG），而肝癌靶向药物如仑伐替尼等可上调肝癌细胞HRG表达并促进其分泌，HRG可诱导肿瘤相关巨噬细胞（TAM）由M2型向M1型极化，并促进CD8+T细胞浸润。基于前期研究结果，我们提出解除肿瘤细胞对HRG表达的抑制作用可显著改善肿瘤免疫抑制微环境的科学假说。为验证假说，本项目拟首先探讨HRG对TAM逆向极化的影响，以及逆向极化的TAM对肿瘤细胞和微环境的调节作用并阐明机制；其次，明确HRG在肝癌发生发展中的作用及其机制以及如何解除肿瘤细胞对HRG表达的抑制作用；最后，探讨诱导肝癌细胞高表达HRG或外源性给予HRG处理后对免疫治疗的影响。据此，阐明HRG在肝癌中的作用及对肿瘤微环境的影响，为临床肝癌的联合治疗策略提供理论依据。

The immunosuppressive state of tumor microenvironment (TME) is a key factor affecting the drug efficacy during hepatocellular carcinoma (HCC) treatment. Our previous results indicated that HRG protein expression was down-regulated in HCC cells, while targeted drugs such as Lenvatinib could promote HRG expression and secretion. Moreover, HRG could induce tumor-associated macrophage (TAM) polarization from M2 to M1 phenotype and enhance the CD8+ T cell infiltration. Based on the previous experiments, we propose a scientific hypothesis that releasing the inhibition of HRG in tumor cells can significantly alleviate the immunosuppressive tumor microenvironment. To verify this hypothesis, the study will firstly clarify the roles of HRG in TAM reverse polarization, followed by exploring the regulatory impacts of M1 macrophages on tumor cells and TME as well as the underlying mechanisms. Secondly, we will explore the molecular functions of HRG in the development and progression of HCC, and explore how to relieve the inhibition of HRG in tumor cells. Finally, the capabilities of high expression of HRG in HCC cells or exogenous HRG treatment on immunotherapy will be investigated. Thus, the study will elucidate the effect of HRG in HCC and its impact on TME, which provides clinically important strategy for combined treatment of HCC.