清华大学蒋宇扬课题组取得一项新突破。他们发现了DNMT抑制通过表观遗传恢复cGAS-STING通路，激活RIG-I/MDA5-MAVS，增强抗肿瘤免疫。相关论文于2025年8月19日发表在《中国药理学报》杂志上。

本研究系统探讨了cGAS-STING通路在肿瘤中的表达模式及其与免疫治疗应答的关系。课题组发现，在大多数乳腺癌和小鼠肿瘤细胞系中，cGAS和STING的表达显著降低或无法检测到，而cGAS和STING的高表达与T细胞浸润增加、PD-L1和PD-1水平升高、免疫治疗反应改善和生存期延长有关。在cGAS-STING缺失的MDA-MB-453细胞中，DNMT抑制剂地西他滨(DAC, 0.05μM)剂量依赖性地通过逆转DNA甲基化介导的沉默来恢复受损通路。

此外，DAC联合化疗药物顺铂通过细胞质DNA积累激活cGAS-STING通路，显著增强MDA-MB-453和MDA-MB-231细胞的抗肿瘤作用。此外，DNMT抑制提高了细胞内dsRNA水平，激活了RIG-I/MDA5-MAVS通路。这些结果表明，DNMT抑制剂可以表观遗传地重编程cGAS-STING通路，激活RIG-I/MDA5-MAVS通路，并与化疗药物联合，协同促进抗肿瘤免疫。总之，本研究确定了cGAS-STING作为免疫治疗反应的潜在预测因子，并强调了一种恢复癌症先天免疫功能的新治疗策略。

据了解，cGAS-STING胞质DNA传感通路是先天免疫应答的关键介质，在抗肿瘤免疫中起重要作用。肿瘤细胞中cGAS和STING的表达常被抑制，表达降低与预后不良和免疫治疗反应较差有关。

附：英文原文

Title: DNMT inhibition epigenetically restores the cGAS-STING pathway and activates RIG-I/MDA5-MAVS to enhance antitumor immunity

Author: Tu, Yao, Zhu, Qing-yun, Huang, Wen-jun, Feng, Sha, Tan, Yu-ling, Li, Lu-lu, Xie, Xin-tong, Li, Qin-yuan, Huang, Shou-hui, Mao, Cheng-zhou, Chu, Bi-zhu, Jiang, Yu-yang

Issue&Volume: 2025-08-19

Abstract: The cGAS-STING cytosolic DNA-sensing pathway is a key mediator of the innate immune response and plays a crucial role in antitumor immunity. The expression of cGAS and STING is often suppressed in tumor cells, and reduced expression is associated with poor prognosis and inferior response to immunotherapy. In this study we systematically investigated the expression pattern of cGAS-STING pathway in tumors and its correlation with immunotherapy response. We showed that the expression of cGAS and STING was significantly decreased or undetectable in most breast cancer and murine tumor cell lines, while high cGAS and STING expression was associated with increased T cell infiltration, elevated PD-L1 and PD-1 levels, improved immunotherapy response and prolonged survival. In cGAS-STING–deficient MDA-MB-453 cells, DNMT inhibitor decitabine (DAC, 0.051μM) dose-dependently restored the impaired pathway by reversing DNA methylation–mediated silencing. Furthermore, DAC combined with a chemotherapeutic agent cisplatin significantly enhanced the antitumor effect in MDA-MB-453 and MDA-MB-231 cells by activating the cGAS-STING pathway through cytoplasmic DNA accumulation. In addition, DNMT inhibition elevated intracellular dsRNA levels and activated the RIG-I/MDA5-MAVS pathway. These results suggest that DNMT inhibitors can epigenetically reprogram the cGAS-STING pathway, activate the RIG-I/MDA5-MAVS pathway, and in combination with chemotherapeutic agents, synergistically promote antitumor immunity. Together, this study identifies cGAS-STING as a potential predictor of immunotherapy response and highlights a novel therapeutic strategy for restoring innate immune function in cancer.

DOI: 10.1038/s41401-025-01639-y

Source: https://www.nature.com/articles/s41401-025-01639-y