A Manganese-based Nano-driver Coordinates Tumor Prevention and Suppression through STING Activation in Glioblastoma.

Glioblastoma (GBM), the most prevalent and aggressive primary malignant brain tumor, exhibits profound immunosuppression and demonstrates a low response rate to current immunotherapy strategies. Manganese cations (Mn 2+ ) directly activate the cGAS/STING pathway and induce the unique catalytic synthesis of 2'3'-cGAMP to facilitate type I IFN production, thereby enhancing innate immunity. Here, a telodendrimer and Mn 2+ -based nano-driver (PLHM) with a small size was developed, which effectively targeted lymph nodes through the blood circulation and exhibited tumor-preventive effects at low doses of Mn 2+ (3.7 mg kg -1 ). On the other hand, the PLHM nano-driver also exhibited apparent anti-tumor effects in GBM-bearing mice via inducing in vivo innate immune responses. The combination of PLHM with doxorubicin nanoparticles (PLHM-DOX NPs) resulted in superior inhibition of tumor growth in GBM-bearing mice due to the synergistic potentiation of STING pathway functionality by Mn 2+ and the presence of cytoplasmic DNA. Our findings demonstrate that PLHM-DOX NPs effectively stimulated innate immunity, promoted dendritic cell maturation, and orchestrated cascaded infiltration of CD8 cytotoxic T lymphocytes within glioblastomas characterized by low immunogenicity. These nano-divers chelated with Mn 2+ show promising potential for tumor prevention and anti-tumor effects on glioblastoma by activating the STING pathway. This article is protected by copyright. All rights reserved.