Nrf2缺失通过GPX2-ICD-DC信号通路将食管鳞癌微环境转化为免疫活跃状态
Nrf2 deficiency converts the ESCC microenvironment into an immunologically active state via the GPX2-ICD-DC signaling path.
摘要(中文译文)
放疗（RT）抵抗仍然是食管鳞状细胞癌（ESCC）面临的重大挑战。尽管已知Nrf2介导抗氧化防御，但其在调节放疗诱导细胞死亡免疫原性中的作用尚不清楚。我们利用条件性敲除Nrf2的基因工程小鼠建立了自发性食管癌模型，并通过单细胞RNA测序分析了肿瘤免疫微环境。在体外，我们使用CRISPR/Cas9介导的Nrf2敲除食管癌细胞系与树突状细胞和T细胞进行共培养实验，以验证免疫激活。此外，利用小鼠皮下肿瘤模型进行了体内验证。单细胞RNA测序（ScRNA-seq）揭示，Nrf2缺失显著重塑了髓系细胞区室，其特征为巨噬细胞从Folr2+向Mrc1+的群体转变以及效应T细胞的扩增。机制上，Nrf2缺失下调了Gpx2的表达，损害了抗氧化防御。这使ESCC细胞对放疗敏感，触发免疫原性细胞死亡（ICD）标志物的释放，包括ATP、HMGB1和表面钙网蛋白（CRT）。在肿瘤-树突状细胞-T细胞共培养系统中，Nrf2缺陷细胞刺激树突状细胞（DCs）分泌IP-10（CXCL10），这对于CD8+ T细胞的募集和激活不可或缺。最后，体内实验证实Nrf2缺失增强了放射敏感性并促进了CD8+ T细胞浸润。我们的研究结果确定了Nrf2-Gpx2轴是ESCC免疫原性的主调控因子。靶向该轴代表了一种有前景的策略，可将“冷”肿瘤转化为“热”环境，从而提高放疗和免疫治疗的疗效。
Abstract
Radiotherapy (RT) resistance remains a significant challenge in esophageal squamous cell carcinoma (ESCC). While Nrf2 is known to mediate antioxidant defense, its role in modulating the immunogenicity of radiotherapy-induced cell death is poorly understood. We established a spontaneous esophageal cancer model using genetically engineered mice with conditional knockout of Nrf2, and analyzed the tumor immune microenvironment by single-cell RNA sequencing. In vitro, we performed co-culture experiments using CRISPR/Cas9-mediated Nrf2-knockout esophageal cancer cell lines with dendritic cells and T cells to validate immune activation. In addition, in vivo validation was conducted using a mouse subcutaneous tumor model. ScRNA-seq revealed that Nrf2 deficiency significantly remodeled the myeloid compartment, characterized by a population shift from Folr2 + to Mrc1 + macrophages and an expansion of effector T cells. Mechanistically, Nrf2 deletion downregulated the expression of Gpx2, impairing antioxidant defenses. This sensitized ESCC cells to RT, triggering the release of immunogenic cell death (ICD) markers, including ATP, HMGB1, and surface calreticulin (CRT). In tumor-DC-T cell co-culture systems, Nrf2-deficient cells stimulated dendritic cells (DCs) to secrete IP-10 (CXCL10), which was indispensable for the recruitment and activation of CD8 + T cells. Finally, in vivo experiments confirmed that Nrf2 deficiency enhanced radiosensitivity and promoted CD8 + T cell infiltration. Our findings identify the Nrf2-Gpx2 axis as a master regulator of immunogenicity in ESCC. Targeting this axis represents a promising strategy to convert "cold" tumors into "hot" environments, thereby improving the efficacy of radiotherapy and immunotherapy.
如何引用
AMA
Yu Liu, Qing Guo, Ming Liu, Dashan Ai, Yun Chen, Qi Liu, et al. Nrf2 deficiency converts the ESCC microenvironment into an immunologically active state via the GPX2-ICD-DC signaling path.. Journal of translational medicine. 2026; doi:10.1186/s12967-026-08323-7.
APA
Yu Liu, Qing Guo, Ming Liu, Dashan Ai, Yun Chen, Qi Liu, et al (2026). Nrf2 deficiency converts the ESCC microenvironment into an immunologically active state via the GPX2-ICD-DC signaling path.. Journal of translational medicine. https://doi.org/10.1186/s12967-026-08323-7
GB/T 7714
Yu Liu, Qing Guo, Ming Liu, Dashan Ai, Yun Chen, Qi Liu, et al. Nrf2 deficiency converts the ESCC microenvironment into an immunologically active state via the GPX2-ICD-DC signaling path.[J]. Journal of translational medicine, 2026 doi:10.1186/s12967-026-08323-7.
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