Zheng Yue, Chen Xiao-Xiao, Zhang Dong-Yang, Wang Wen-Jin, Peng Kun, Li Zhi-Yuan, Mao Zong-Wan, Tan Cai-Ping
MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, School of Chemistry, State Key Laboratory of Oncology in South China, Sun Yat-Sen University Guangzhou 510006 P. R. China
Chem Sci. 2023 Jun 6;14(25):6890-6903. doi: 10.1039/d3sc01737k. eCollection 2023 Jun 28.
The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon (STING) pathway is a key mediator of innate immunity involved in cancer development and treatment. The roles of mitochondrial DNA (mtDNA) in cancer immunotherapy have gradually emerged. Herein, we report a highly emissive rhodium(iii) complex (Rh-Mito) as the mtDNA intercalator. Rh-Mito can specifically bind to mtDNA to cause the cytoplasmic release of mtDNA fragments to activate the cGAS-STING pathway. Moreover, Rh-Mito activates the mitochondrial retrograde signaling by disturbing the key metabolites involved in epigenetic modifications, which alters the nuclear genome methylation landscape to influence the expression of genes related to immune signaling pathways. Finally, we demonstrate that ferritin-encapsulated Rh-Mito elicits potent anticancer activities and evokes intense immune responses by intravenous injection. Overall, we report for the first time that small molecules targeting mtDNA can activate the cGAS-STING pathway, which gives insights into the development of biomacromolecule-targeted immunotherapeutic agents.
环磷酸鸟苷-腺苷酸合成酶（cGAS）-干扰素基因刺激蛋白（STING）通路是参与癌症发生发展和治疗的固有免疫的关键介质。线粒体DNA（mtDNA）在癌症免疫治疗中的作用已逐渐显现。在此，我们报道了一种高发光性的铑（III）配合物（Rh-Mito）作为mtDNA嵌入剂。Rh-Mito能特异性结合mtDNA，导致mtDNA片段释放到细胞质中，从而激活cGAS-STING通路。此外，Rh-Mito通过干扰参与表观遗传修饰的关键代谢物来激活线粒体逆行信号，进而改变核基因组甲基化格局，影响与免疫信号通路相关基因的表达。最后，我们证明，通过静脉注射，铁蛋白包裹的Rh-Mito能引发强大的抗癌活性并激发强烈的免疫反应。总体而言，我们首次报道靶向mtDNA的小分子可激活cGAS-STING通路，这为生物大分子靶向免疫治疗药物的开发提供了思路。
