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

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 (CaCO3) 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 CaCO3 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 scaffoldMSA-2 αB7-H3-MP represents a promising localized immunotherapy approach for the treatment of bone metastasis.