Revolutionizing Bone Tumor Therapy: Biodegradable Magnesium Implant Triggers cGAS‐STING‐Dependent Synergy of Autophagic Cell Death and Alkaline Metabolic Collapse

Abstract Bone tumors are challenging to eradicate, with conventional limb‐salvage surgeries often leading to high rates of recurrence, metastasis, and severe functional impairments due to large bone defects. Traditional therapies struggle to balance tumor elimination with bone preservation and functional restoration. This study presents a novel therapeutic strategy utilizing high‐purity biodegradable magnesium (Mg) implants, which induce dual‐mode bone tumor death orchestrated by the cGAS‐STING pathway. Released Mg ions trigger autophagic cell death through TRPM7‐mediated uptake, with cGAS‐STING promoting LC3 lipidation by supplying STING‐laden ERGIC membranes. Simultaneously, alkaline degradation byproducts disrupt tumor metabolism by suppressing glycolysis and oxidative phosphorylation, with cGAS‐STING further targeting hexokinase 2 (HK2) to amplify metabolic collapse. This coordinated mechanism reshapes the tumor microenvironment, promoting M1 macrophage polarization, CD8 + T cell infiltration, and enhanced intratumoral IFN‐γ secretion, fostering a robust, sustained immune response. The therapeutic efficacy and biosafety of Mg implants are validated in murine osteosarcoma, patient‐derived xenografts, and VX2 rabbit bone tumor models, demonstrating significant tumor suppression and prolonged survival without systemic toxicity. This work highlights the multifunctional capabilities of biodegradable Mg implants, integrating autophagic death, metabolic suppression, and immune modulation through cGAS‐STING coordination, presenting a promising and clinically translatable strategy for advanced bone tumor therapy.