核受体 Nur77 在许多癌症中发挥着矛盾的作用。然而，Nur77 是否抑制食管鳞状细胞癌 (ESCC) 生长并影响针对 ESCC 的免疫反应尚未确定。本研究使用人 ESCC 细胞系、定量实时聚合酶链反应 (PCR)、细胞增殖和集落形成测定、流式细胞术分析、蛋白质印迹和动物模型研究了 Nur77 在 ESCC 中的功能作用。使用双荧光素酶报告基因测定、染色质免疫沉淀分析和功能拯救实验验证了 Nur77 控制的靶基因。为了检验 Nur77 的临床重要性，对 72 个人类原发性 ESCC 组织进行了免疫组织化学分析。总而言之，这些发现表明，无论是在体外还是体内，Nur77 都显着降低了 ESCC 细胞的生长并引发细胞凋亡。 Nur77 直接与干扰素调节因子 1 (IRF1) 启动子相互作用，抑制其在 ESCC 中的活性。使用细胞孢子素 B (CsnB) 药理诱导 Nur77 可在体外和体内抑制 ESCC 细胞增殖并促进细胞凋亡。此外，CsnB 增加 CD8 T 细胞浸润和细胞毒性，从而抑制免疫活性小鼠模型中 ESCC 肿瘤的形成。 ESCC组织中Nur77表达下调，IRF1表达上调；此外，它们的表达水平呈负相关。 IRF1 和 Nur77 与总生存期密切相关。这些发现表明，Nur77 靶向并调节 IRF1/PD-L1 轴，作为 ESCC 的肿瘤抑制因子。 Nur77 过表达下调 IRF1 抑制 ESCC 进展并增强抗 PD-1 治疗效果的调节机制图解摘要。© 2024。作者。

The nuclear receptor Nur77 plays paradoxical roles in numerous cancers. However, whether Nur77 inhibits esophageal squamous cell carcinoma (ESCC) growth and affects immunological responses against ESCC has not been determined. The functional role of Nur77 in ESCC was investigated in this study using human ESCC cell lines, quantitative real-time polymerase chain reaction (PCR), cell proliferation and colony formation assays, flow cytometry analysis, western blotting and animal models. The target gene controlled by Nur77 was verified using dual-luciferase reporter assays, chromatin immunoprecipitation analysis and functional rescue experiments. To examine the clinical importance of Nur77, 72 human primary ESCC tissues were subjected to immunohistochemistry. Taken together, these findings showed that, both in vitro and in vivo, Nur77 dramatically reduced ESCC cell growth and triggered apoptosis. Nur77 directly interacts with the interferon regulatory factor 1 (IRF1) promoter to inhibit its activity in ESCC. Pharmacological induction of Nur77 using cytosporone B (CsnB) inhibited ESCC cell proliferation and promoted apoptosis both in vitro and in vivo. Furthermore, CsnB increased CD8+ T-cell infiltration and cytotoxicity to inhibit the formation of ESCC tumors in an immunocompetent mouse model. In ESCC tissues, Nur77 expression was downregulated, and IRF1 expression was increased; moreover, their expression levels were negatively related. IRF1 and Nur77 were strongly correlated with overall survival. These findings suggested that Nur77 targets and regulates the IRF1/PD-L1 axis to serve as a tumor suppressor in ESCC. Graphical abstract of the regulatory mechanism of Nur77 overexpression downregulates IRF1 in the inhibition of ESCC progression and enhance anti-PD-1 therapy efficacy.© 2024. The Author(s).