食管鳞癌中UBQLN2调控cGAS/STING的机制及其在免疫治疗中的作用研究

cGAS/STING是架起固有和适应性免疫桥梁的关键信号分子，在克服肿瘤免疫治疗耐受中发挥着重要作用，但其调控机制尚需深入研究。我们的前期工作发现：食管鳞癌中泛素样蛋白2（UBQLN2）很可能是调控cGAS/STING的重要分子。本研究拟通过肿瘤细胞与免疫细胞共培养实验、人免疫系统重建小鼠移植瘤模型和接受抗PD-1免疫治疗食管鳞癌患者及其组织标本，进一步分析UBQLN2、cGAS/STING、食管鳞癌免疫原性以及抗PD-1免疫治疗疗效之间的关系；从直接激活和间接激活两个方面研究UBQLN2调控STING的分子机制；探寻UBQLN2调控的cGAS/STING信号分子在食管鳞癌免疫治疗中的作用。我们的工作首次把UBQLN2的功能研究拓展至肿瘤免疫治疗，有望在阐明cGAS/STING分子调控机理的同时，为深入了解食管鳞癌免疫检查点抑制剂治疗耐受机制及开发有前景的联合治疗策略提供理论依据。

cGAS/STING is a key molecule that bridges the innate and adaptive immunity. The success of cGAS/STING in disrupting the tolerance of cancer immunotherapy highlights the need to understand the molecular regulation of cGAS/STING. In our previous study, we found that Ubiquilin 2 (UBQLN2) regulated STING in esophageal squamous cell carcinoma (ESCC).In this study, we attempt to analyze the relationship among UBQLN2, cGAS/STING, the immunogenicity of ESCC, and the therapeutic effect of anti-PD-1. The mechanism of UBQLN2 in regulating cGAS/STING in ESCC will be investigated from two aspects of direct and indirect activation. Finally, we will evaluate the role of UBQLN2-regulated cGAS/STING signaling pathway in the treatment of ESCC with immune checkpoint inhibitor. Co-culture of ESCC cells, dendritic cells and T cells, ESCC xenograft in humanized B-NDG mice, and histological samples from ESCC patients will be used to verify the hypothesis. Our work brings UBQLN2 into the field of cancer immunotherapy for the first time, which is expected to disclose the molecular regulation of cGAS/STING and the tolerance mechanism of immune checkpoint inhibitor therapy, and develop a promising combined therapy strategy for patients with ESCC.