Stabilization of G-quadruplex (G4) structures in mitochondria leads to the damage of mitochondrial DNA (mtDNA), making mtDNA G4s a promising target in the field of cancer therapy in recent years. Damaged mtDNA released into the cytosol can stimulate cytosolic DNA-sensing pathways, and cGAS-STING pathway is a typical one with potent immunostimulatory effects. A few small molecule ligands of mtDNA G4s are identified with antitumor efficacy, but little is known about their results and mechanisms on immunomodulation. In this study, we engineered a series of triphenylamine-based analogues targeting mtDNA G4s, and was determined as the most promising compound. Cellular studies indicated that caused severe mtDNA damage. Then, damaged mtDNA stimulated cGAS-STING pathway, resulting in the following cytokine production of tumor cells and the maturation of DCs. In vivo experiments certified that exerted suppressive influences on tumor growth and metastasis in 4T1 cell-bearing mice by the regulation of TME, including the remodeling of macrophages and the activation of T cells. To our knowledge, it is the first time to report a ligand targeting mtDNA G4s to activate the cGAS-STING immunomodulatory pathway, providing a novel strategy for the future development of mtDNA G4-based antitumor agents.

中文翻译：

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发现基于三苯胺的配体，该配体靶向线粒体 DNA G 四链体并激活 cGAS-STING 免疫调节途径

线粒体中G四链体（G4）结构的稳定会导致线粒体DNA（mtDNA）的损伤，使得mtDNA G4s成为近年来癌症治疗领域有希望的靶点。受损的线粒体DNA释放到细胞质中可以刺激细胞质DNA传感途径，而cGAS-STING途径是一种典型的具有有效免疫刺激作用的途径。 mtDNA G4 的一些小分子配体已被鉴定具有抗肿瘤功效，但对其免疫调节的结果和机制知之甚少。在这项研究中，我们设计了一系列针对 mtDNA G4 的基于三苯胺的类似物，并被确定为最有前途的化合物。细胞研究表明这会造成严重的线粒体DNA损伤。然后，受损的mtDNA刺激cGAS-STING通路，导致肿瘤细胞产生后续细胞因子和DC成熟。体内实验证明，通过调节TME，包括巨噬细胞的重塑和T细胞的激活，对4T1细胞小鼠的肿瘤生长和转移产生抑制作用。据我们所知，这是首次报道靶向mtDNA G4的配体激活cGAS-STING免疫调节途径，为未来开发基于mtDNA G4的抗肿瘤药物提供了新的策略。