STING stimulation via supramolecular prodrug hydrogel boosts innate-adaptive immune cross-talk to prevent glioblastoma recurrence.

Abstract

Glioblastoma multiforme (GBM), the most aggressive primary brain tumor, demonstrates persistent resistance to immunotherapy due to its profoundly immunosuppressive microenvironment and markedly limited T cell infiltration. In this context, we engineered a STING agonist-incorporated prodrug hydrogel that orchestrates dual activation of innate and adaptive immunity to prevent postoperative GBM recurrence. We found that this in situ-forming hydrogel integrates seamlessly with tumor resection procedures, serves as a drug depot for sustained tumoral releases of therapeutic agents, and thus reprograms the tumor microenvironment by promoting M1 macrophage polarization, suppressing regulatory T cell activity, and enhancing cytotoxic T lymphocyte infiltration, thereby establishing a robust antitumor immune response. As a postoperative adjuvant therapy, the hydrogel effectively inhibits orthotopic GBM recurrence and extends animal survival while establishing durable immune memory against tumor rechallenge. Our findings demonstrate the translational potential of immunologically engineered hydrogels for STING-activated immunotherapy in preventing postresection GBM recurrence.