Ultrasound-responsive metal–organic framework-based nanosystem for sonodynamic therapy/amplified ferroptosis/IDO-blockade osteosarcoma immunotherapy

•MFePCN@1-MT target tumor cells to alleviate side effects.•MFePCN@1-MT has GSHOx activity, CAT activity and sonic sensitivity.•MFePCN@1-MT induce ROS generation, ferroptosis, and responsive release of 1-MT.•The synergistic therapy amplifies the ICD effect and induces a robust immune response. The metastasis and recurrence of osteosarcoma (OS) are significant challenges in its clinical management. Tumor immunogenic cell death (ICD)-induced immunotherapy has been widely investigated to solve these problems. However, achieving sufficient ICD and a robust immune response is challenging for nanoparticle-based OS immunotherapy. Here, we report an ultrasound-responsive metal–organic framework-based nanosystem (MFePCN@1-MT) with sonodynamic therapy (SDT) and 1-methyltryptophan (1-MT) responsive release properties. Under ultrasound irradiation, the nanosystem induces reactive oxygen species (ROS) generation, ferroptosis, and the responsive release of 1-MT, which competitively inhibits indoleamine-2,3-dioxygenase (IDO), promotes further ROS accumulation, and amplifies ferroptosis. Notably, SDT/amplified ferroptosis/IDO blockade synergistically kills OS cells, maximizes the amplified ICD effect, activates dendritic cells (DCs) maturation, inhibits regulatory T lymphocytes (Tregs), and triggers CD4+ T-cell and CD8+ T-cell immune responses. Thus, this nanosystem synergistically inhibits K7M2 primary tumors via SDT/amplified ferroptosis/IDO blockade. In addition, the nanosystem enhances the ICD effect, modulates the immunosuppressive microenvironment, promotes immunity against solid tumors, and inhibits distant metastatic tumor growth. This study combines SDT/amplified ferroptosis/IDO blockade into a single nanomedicine and presents a new strategy for OS immunotherapy.