A Manganese Phosphate Nanocluster Activates the cGAS‐STING Pathway for Enhanced Cancer Immunotherapy

Targeting the stimulator of interferon genes (STING) pathway with cyclic dinucleotides (CDNs), natural STING agonists, is a promising immunotherapeutic strategy for cancer. However, clinical application CDNs as therapeutics greatly hindered by their intrinsic properties including negative charges, small molecular weight, and high susceptibility to enzymatic degradation. Mn2+ ions have been recently discovered directly activate GMP-AMP (cGAMP) synthase (cGAS) augment cGAMP-STING binding affinity. Here, PEGylated manganese(II) phosphate (MnP-PEG) nanocluster developed biocompatibility potent capacity stimulate cGAS-STING pathway. MnP-PEG nanoclusters immature bone marrow-derived dendritic cells (DCs) leading 57.3- 13.3-fold higher production β interleukin-6 than free cGAMP, respectively. The activation likely due efficient cellular internalization DCs acid-triggered release in endolysosomes. Intratumoral administration markedly enhances tumor infiltration well maturation macrophages, promotes cytotoxicity T killer tumor. combination checkpoint inhibitor leads significant regression B16F10 murine melanoma model without any overt toxicities.