Mitochondrial DNA-Mediated Intercellular Communication via Extracellular Vesicles Under Hypoxic Stress to Drive HCC Progression.

Immunotherapy has opened new opportunities for the therapy of hepatocellular carcinoma (HCC), but is limited by the immunosuppressive microenvironment. Recent studies have reported that abnormal mitochondrial DNA (mtDNA) stress in tumor cells acts as an intercellular communication signal capable of affecting the tumor itself as well as the microenvironment, but the pathways by which mtDNA drives this process are currently unknown. In this study, we found that mtDNA is involved in hypoxia-derived EVs-mediated macrophage M2 phenotypic polarization promoting HCC progression. In vitro and in vivo experiments demonstrated that hypoxia promotes mtDNA release by enhancing mitochondrial quality control (MQC) signaling and subsequent exocytosis to macrophage via EVs. EVs carrying mtDNA activate macrophage cGAS/STING/NF-κB pathway and promote M2 phenotypic polarization. In addition, we have modified the drug by using a nanodelivery system to make it tumor-targeted and effective in inhibiting tumor growth in vivo. Taken together, our study reveals a critical role for EVs-mtDNA in the formation of the immunosuppressive microenvironment in HCC under hypoxia and provides new evidence and solutions to improve sensitivity to immunotherapy for HCC.