Xia Lintao, Yan Xiuli, Zhang Hui
Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, China.
Biochim Biophys Acta Rev Cancer. 2025 Feb;1880(1):189249. doi: 10.1016/j.bbcan.2024.189249. Epub 2024 Dec 17.
Mitochondrial DNA (mtDNA), a circular double-stranded DNA located within mitochondria, plays a pivotal role in mitochondrial-induced innate immunity, particularly via the cyclic GMP-AMP synthase (cGAS)-STING pathway, which recognizes double-stranded DNA and is crucial for pathogen resistance. Recent studies elucidate the interplay among mtDNA, the cGAS-STING pathway, and neutrophil extracellular traps (NETs) in the context of cancer. mtDNA uptake by recipient cells activates the cGAS-STING pathway, while mtDNA leakage reciprocally regulates NET release, amplifying inflammation and promoting NETosis, a mechanism of tumor cell death. Autophagy modulates these processes by clearing damaged mitochondria and degrading cGAS, thus preventing mtDNA recognition. Tumor microenvironmental factors, such as metabolic reprogramming and lipid accumulation, induce mitochondrial stress, ROS production, and further mtDNA leakage. This review explores strategies in cancer drug development that leverage mtDNA leakage to activate the cGAS-STING pathway, potentially converting 'cold tumors' into 'hot tumors,' while discussing advancements in targeted therapies and proposing new research methodologies.
线粒体DNA（mtDNA）是一种位于线粒体内的环状双链DNA，在由线粒体引发的固有免疫中发挥关键作用，特别是通过环状GMP-AMP合酶（cGAS）-干扰素基因刺激蛋白（STING）途径，该途径可识别双链DNA，对病原体抗性至关重要。最近的研究阐明了在癌症背景下mtDNA、cGAS-STING途径和中性粒细胞胞外陷阱（NETs）之间的相互作用。受体细胞摄取mtDNA会激活cGAS-STING途径，而mtDNA泄漏则会相互调节NET释放，放大炎症并促进NETosis（一种肿瘤细胞死亡机制）。自噬通过清除受损线粒体和降解cGAS来调节这些过程，从而防止mtDNA被识别。肿瘤微环境因素，如代谢重编程和脂质积累，会诱导线粒体应激、活性氧生成以及进一步的mtDNA泄漏。本综述探讨了癌症药物开发中的策略，这些策略利用mtDNA泄漏来激活cGAS-STING途径，有可能将“冷肿瘤”转化为“热肿瘤”，同时讨论了靶向治疗的进展并提出了新的研究方法。
