Abstract
Mitochondrial DNA (mtDNA) functions as an endogenous danger-associated molecular pattern that broadly activates the cGAS-STING pathway to potentiate antitumor immunotherapy. However, inefficient mtDNA release severely limits its ability to robustly activate downstream immune responses. Recent studies reveal that ferroptosis can trigger mtDNA release from damaged mitochondria into the cytosol, thereby stimulating antitumor immunity. Thus, precisely modulating mitochondria-associated ferroptosis to promote mtDNA-dependent cGAS-STING activation represents a promising strategy for enhancing immunotherapy. Here, we engineered a mitochondria-targeted MXene@MnO(2)-TPP Schottky heterojunction that integrates sonosensitization, ferroptosis induction, and immune activation for synergistic therapy. This nanoplatform not only directly generates ROS to trigger tumor cell ferroptosis but also amplifies ferroptosis via an MCU-dependent Ca(2+) influx pathway. Furthermore, it dual-activates the cGAS-STING pathway through released mtDNA and Mn(2+), stimulating type I interferon production and eliciting systemic antitumor immunity. In vitro and in vivo studies demonstrate robust tumor suppression and prolonged survival in osteosarcoma-bearing mice. Our work proposes an innovative "ferroptosis-mtDNA-immunotherapy" paradigm, offering a promising strategy for osteosarcoma treatment.