An Implantable Scaffold Sequentially Releasing STING Agonist and B7‐H3 Antibody for Bone Metastasis Immunotherapy

ABSTRACT Immune checkpoint blockade (ICB) therapy has revolutionized cancer treatment, yet it remains largely ineffective against bone metastases. The immunosuppressive bone marrow microenvironment is a major barrier to ICB success in bone metastasis. Herein, we developed an implantable dual‐drug depot using a gelatin methacryloyl (GelMA) scaffold to prevent tumor recurrence and progression following surgical resection. The GelMA scaffold is co‐loaded with MSA‐2, a non‐nucleotide agonist of stimulator of interferon genes (STING), and calcium carbonate (CaCO 3 ) microparticles (MPs) encapsulating B7‐H3 antibodies (αB7‐H3‐MPs). After implantation at the bone metastasis site, the scaffold provides sustained releases of MSA‐2 and αB7‐H3‐MPs. MSA‐2 is released first to activate the STING signaling pathway, triggering interferon secretion, reprogramming immunosuppressive cells, and promoting effector T cell infiltration and activation. Subsequently, dissolution of CaCO 3 microparticles in the acidic tumor microenvironment facilitates the subsequent release of αB7‐H3, which blocks the B7‐H3 checkpoint upregulated by STING activation and prevents T‐cell exhaustion. This sequential release strategy was validated in multiple bone metastasis models, confirming its ability to produce a sustained and potent local antitumor immune response while reducing systemic toxicity associated with STING agonists and ICB drugs. Therefore, the scaffold MSA‐2 αB7‐H3‐MP represents a promising localized immunotherapy approach for the treatment of bone metastasis.