A manganese-phenolic network platform amplifying STING activation to potentiate MRI guided cancer chemo-/chemodynamic/immune therapy

Low immune infiltration severely hinders the efficacy of cancer immunotherapy. Here, we developed a manganese-phenolic network platform (TMPD) to boost antitumor immunity via a stimulator of interferon gene (STING)-amplified activation cascade. TMPD is based on doxorubicin (DOX)-loaded PEG-PLGA nanoparticles and further coated with manganese (Mn2+)-tannic acid (TA) networks. Mechanistically, DOX-based chemotherapy and Mn2+-mediated chemodynamic therapy effectively promoted immunogenic cell death (ICD), characterized by abundant damage-associated molecular pattern (DAMP) exposure, which subsequently enhanced dendritic cells' (DCs) presentation of antigens. DOX-elicited DNA damage simultaneously caused cytoplasmic leakage of intracellular double-stranded DNA (dsDNA) as the STING signal initiator, while Mn2+ mediated significant upregulation in the expression of a STING pathway-related protein thereby amplifying the STING signal. Systemic intravenous administration of TMPD remarkably promoted DC maturation and CD8+ T cell infiltration, thus eliciting strong antitumor effects. Meanwhile, the released Mn2+ could serve as a contrast agent for tumor-specific T1-weighted magnetic resonance imaging (MRI). Moreover, TMPD combined with immune checkpoint blockade (ICB) immunotherapy significantly inhibited tumor growth and lung metastasis. Collectively, these findings indicate that TMPD has great potential in activating robust innate and adaptive immunity for MRI guided cancer chemo-/chemodynamic/immune therapy.