Promoting Endogenous Danger Signals Accumulation by a Hierarchical Nanoinducer for Amplifying STING Pathway Activation-Mediated Tumor Immunotherapy

Given the clinical limitations of exogenous stimulators of interferon genes (STING) agonists in vivo, activating the cGAS-STING pathway through endogenous danger signals (EDSs) represents a promising alternative approach. Notably, effective activation of cGAS-STING pathway is critically dependent on intracellular EDSs levels. Herein, we report a pH-responsive hierarchical nanoinducer (FGMC) by encapsulating ferritin loaded with glucose oxidase/MK571 (ABCC1 transporter inhibitor) (FGM) into the MK571-Co²⁺ (MC) coordination shell. FGMC induces pyroptosis and accumulation of EDSs in tumor cells by disturbing intracellular homeostasis, thereby enhancing cGAS-STING pathway activation for immunotherapy. Within the tumor microenvironment, FGMC disrupts intracellular homeostasis of tumor cells through its enzymatic activity, leading to pyroptosis-mediated mitochondrial damage and mitoDNA release. Furthermore, the inhibition of glucose/NSUN2/TREX2 axis and ABCC1 transporter enhances intracellular accumulation of dsDNA and cyclic GMP-AMP, potently activating the cGAS-STING pathway. Late in pyroptosis, the dsDNA released from dead tumor cells activates the cGAS-STING pathway in dendritic cells. These effects evoke strong immunity to inhibit tumor growth and metastasis. This study highlights the potential of this hierarchical nanoinducer as an alternative to conventional STING.