The circular GMP-AMP synthase-interferon regulatory factor (cGAS-STING) pathway is the core driving force for innate immune activation, and manganese ions (Mn2+) have recently been confirmed as a potent regulator of this signaling axis. However, the application of Mn2+ is limited by its rapid clearance, non-specific distribution, and potential neurotoxicity. Inspired by the unique chemical structure and biological function of ATP, we propose an ATP-Mn coordination nanoparticle (ATP-Mn) for promoting cGAS-STING activation and anti-tumor immunity. We demonstrated that the phosphate group of ATP can coordinate with Mn2+, and after lipid coating, it forms stable and clearly defined nanoparticles. ATP-Mn CNP significantly enhances the expression of cGAS-STING-related genes and activates the corresponding signal cascade, effectively transforming macrophages from tumor-supportive M2 polarization to anti-tumor M1 phenotype. In vivo anti-tumor studies showed that ATP-Mn nuclear cell inhibitors significantly inhibited tumor growth and reprogrammed macrophages in tumors and draining lymph nodes, thereby promoting the infiltration of cytotoxic lymphocytes into the tumor. ATP-Mn CNP combined with immune checkpoint inhibitors achieved a 37.5% tumor eradication rate in the MC38 mouse model and significantly prolonged the survival of mice. This study established an ATP-driven coordination strategy, using ATP as a component and immunostimulant, to enhance Mn-mediated STING activation. This study was published in Bioactive Materials under the title "ATP-driven STING activation of manganese-coordinated nanoagonist to enhance antitumor immunity".
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DOI: 10.1016/j.bioactmat.2026.02.012