A Manganese‐Based Nanodriver Coordinates Tumor Prevention and Suppression through STING Activation in Glioblastoma

Abstract 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 nanodriver (PLHM) with a small size is developed, which effectively target lymph nodes through the blood circulation and exhibit tumor‐preventive effects at low doses of Mn 2+ (3.7 mg kg −1 ). On the other hand, the PLHM nanodriver also exhibits apparent antitumor effects in GBM‐bearing mice via inducing in vivo innate immune responses. The combination of PLHM with doxorubicin nanoparticles (PLHM‐DOX NPs) results 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. These findings demonstrate that PLHM‐DOX NPs effectively stimulate innate immunity, promote dendritic cell maturation, and orchestrate cascaded infiltration of CD8 cytotoxic T lymphocytes within glioblastomas characterized by low immunogenicity. These nanodivers chelated with Mn 2+ show promising potential for tumor prevention and antitumor effects on glioblastoma by activating the STING pathway.