Abstract

Abstract Osteosarcoma (OS), a highly aggressive bone tumor, presents significant challenges in terms of effective treatment. We identified that cellular autophagy was impaired within OS by comparing clinical OS samples through bioinformatic analyses and further validated the inhibition of mitochondrial autophagy in OS at the transcriptomic level. Based on this finding, we investigated the therapeutic potential of a dual functional metal nanoplatform (MnSx) to facilitate a transition from the protective effect of low-level autophagy in OS to the killing effect of high-level autophagy in OS. MnSx facilitated intracellular H2S generation via endocytosis, leading to the S-sulfhydration of ubiquitin-specific peptidase 8 (USP8) and subsequent promotion of mitochondrial autophagy in vitro. Additionally, MnSx activated the cGAS/STING pathway, further enhancing the cellular autophagic response and accelerating tumor cell death. Moreover, it was demonstrated in vivo that MnSx, on the one hand, mediated the activation of tumor autophagy by USP8 via intracellular H2S, while Mn2+ promoted the maturation of dendritic cells, activated cytotoxic T lymphocytes and contributed to tumor eradication. Such tumor killing could be suppressed by the autophagy inhibitor chloroquine. Importantly, synergistic combination therapy with immune checkpoint inhibitors showed promise for achieving complete remission of OS. This study highlights the potential of MnSx as a dual-functional therapeutic platform for osteosarcoma treatment and offers novel directions for future research in this field.