肿瘤如何改造微环境促进T细胞耗竭是研究热点，但内在机制仍不清楚。我们研究发现癌旁巨噬细胞（MΦ）分布和肝癌预后密切相关；高尔基体蛋白GOLM1通过囊泡样结构参与蛋白分选和再分布。临床组织标本分析显示GOLM1高表达常伴有MΦ密度增加，PD-L1表达升高，CD8+T细胞膜抑制性受体增加，细胞数量减少，杀伤肿瘤能力降低。GOLM1通过Rab27参与外泌体调节，PD-L1和GOLM1相互作用减少降解并在外泌体富集。进一步将通过共培养、CyTOF、Cre-LoxP、CO-IP、激光共聚焦、体内试验等明确肝癌外泌体中GOLM1进入MΦ后促进CSF1R再循环和在细胞膜上的重新分布，提高MΦ对CSF1的应答。这一正反馈机制加速富集有PD-L1的外泌体进入募集到肿瘤的MΦ内并高表达，加快T细胞耗竭，促进肝癌生长转移。探索PD-L1单抗、CSF1R抑制剂、MΦ清除剂联合提高肝癌治疗效果的可行性。

Hepatocellular carcinoma is usually developed on the basis of chronic hepatitis. T cell depletion is prone to occur under the influence of persistent antigen and inflammation. Our previous study found for the first time that Golgi membrane protein 1 (GOLM1), by participating in vesicle formation, promotes endocytic transport of EGF receptors to the cell membrane, thereby evading degradation and promoting metastasis . It was also found that the expression level of CSF1 and the density of macrophages in adjacent liver tissues independently affected the OS and DFSl of patients after radical resection . Compared with the stromal cells, the expression of PD-L1 was lower in hepatocellular carcinoma cells, and the effect of PD-L1 monoclonal antibody was limited. In human hepatocellular carcinoma tissues, GOLM1 increased with high PD-L1 expression, high macrophages density, significantly fewer CD8+ T cells with increased expression of inhibitory receptors and lower activity. The results of the mouse model suggested a similar change in macrophages and T cells in the cancer tissue after GOLM1 knockdown. Mass spectrometry indicated that GOLM1 may regulate secretion of exosomes by binding to Rab27. It was found that GOLM1 can co-localize with PD-L1 and CD63, and the interaction reduced PD-L1 degradation and promote its enrichment in exosomes. By using advanced methods including co-culture, CyTOF, Cre-LoxP , Co-IP, laser confocal, in vivo study, etc, we will further specify that once transferred into macrophage, GOLM1 can promote recirculation of CSF1 receptor and increase the endocytosis function of macrophages. This positive feedback caused sensitive response of macrophages to CSF1, which promoting high intake of exosomes carrying PD-L1 to macrophages. HCC, on the basis of up-regulating the expression of PD-L1 on macrophage, accelerates T cell exhaustion and promotes the growth and metastasis finally. On the basis of the mechanism study, we will explore the effects of treatment with the combination of PD-L1 monoclonal antibody, CSF1 receptor inhibitors and macrophage scavenger on the growth and metastasis of hepatocellular carcinoma.