PDF(Pubmed)
Abstract：
Mitochondrial membrane remodeling can trigger the release of mitochondrial DNA (mtDNA), leading to the activation of cellular oxidative stress and immune responses. While the role of mitochondrial membrane remodeling in promoting inflammation in hepatocytes is well-established, its effects on tumors have remained unclear. In this study, we designed a novel Pt(IV) complex, OAP2, which is composed of oxaliplatin (Oxa) and acetaminophen (APAP), to enhance its anti-tumor effects and amplify the immune response. Our findings demonstrate that OAP2 induces nuclear DNA damage, resulting in the production of nuclear DNA. Additionally, OAP2 downregulates the expression of mitochondrial Sam50, to promote mitochondrial membrane remodeling and trigger mtDNA secretion, leading to double-stranded DNA accumulation and ultimately synergistically activating the intracellular cGAS-STING pathway. The mitochondrial membrane remodeling induced by OAP2 overcomes the limitations of Oxa in activating the STING pathway and simultaneously promotes gasdermin-D-mediated cell pyroptosis. OAP2 also promotes dendritic cell maturation and enhances the quantity and efficacy of cytotoxic T cells, thereby inhibiting cancer cell proliferation and metastasis. Briefly, our study introduces the first novel small-molecule inhibitor that regulates mitochondrial membrane remodeling for active immunotherapy in anti-tumor research, which may provide a creative idea for targeting organelle in anti-tumor therapy.
摘要：
线粒体膜重塑可以触发线粒体DNA（mtDNA）的释放，导致细胞氧化应激和免疫反应的激活。虽然线粒体膜重塑在促进肝细胞炎症中的作用是公认的，其对肿瘤的影响尚不清楚。在这项研究中,我们设计了一种新型的Pt(IV)配合物，OAP2，由奥沙利铂（Oxa）和对乙酰氨基酚（APAP）组成，增强其抗肿瘤作用，放大免疫反应。我们的发现表明OAP2诱导核DNA损伤，导致核DNA的产生。此外,OAP2下调线粒体Sam50的表达，促进线粒体膜重塑，触发mtDNA分泌，导致双链DNA积累并最终协同激活细胞内cGAS-STING途径。OAP2诱导的线粒体膜重塑克服了Oxa激活STING途径的局限性，同时促进gasdermin-D介导的细胞焦亡。OAP2还促进树突状细胞成熟，增强细胞毒性T细胞的数量和功效，从而抑制癌细胞增殖和转移。简而言之，我们的研究介绍了第一个新的小分子抑制剂，调节线粒体膜重塑的主动免疫疗法在抗肿瘤研究，这可能为靶向细胞器在抗肿瘤治疗中提供了一个创新的思路。
