Smart Organic–Inorganic Copolymer Nanoparticles Distinguish Between Microglia and Cancer Cells for Synergistic Immunotherapy in Glioma

Abstract The stimulator of interferon genes (STING) pathway has emerged as a new immunotherapy strategy with potent local stimulation specificity, showing promising potential to counteract the immunosuppression in glioma. Herein, a tumor microenvironment (TME) responsive nanoagonists are developed based on an organic–inorganic copolymer composed of the polymer PC6AB coupled with manganous phosphate ionic oligomers (MnP). The degradation of nanoagonists into PC6AB and MnP in the acidic TME enables spatiotemporal control of their delivery to tumor cells and immune cells, respectively. PC6AB with membranolytic activity selectively interacts with tumor cell membranes to induce immunogenic cell death, while manganese metal can activate the STING pathway in immune cells and trigger downstream immunostimulatory signals. Nanoagonists can stimulate robust antitumor immunity after local injection into the brain extracellular space (ECS), showing significant therapeutic efficacy in mouse glioma. Nanoagonists can achieve spatiotemporal orchestration of STING activation in response to TME and enhance immune response against “cold” solid tumors, providing a promising approach for clinical immunotherapy.