Synergistic Activation of Immunogenic Cell Death and the cGAS-STING Pathway by Engineered Zinc/Manganese-Based Metal-Organic Framework Nanoplatforms for Colon Cancer Immunotherapy.

The cyclic guanosine monophosphate (GMP)-adenosine monophosphate (AMP) synthase-stimulator of interferon genes (cGAS-STING) pathway is crucial for tumor immunity. However, activation of the cGAS-STING pathway alone is seldom sufficient to eliminate established tumors. Here, we report the engineering of zinc/manganese (Zn/Mn)-based metal-organic framework (MOF) nanoparticles, that is, AMP@Zn/Mn-MOF, comprising Zn/Mn-MOF nanoparticles as the carrier and the STING agonist c-di-AMP diammonium as the therapeutic drug for reinforcing antitumor immune responses. These therapeutic nanoplatforms can significantly activate the cGAS‒STING pathway and facilitate the innate immune response. Furthermore, the peroxidase (POD)-mimetic and glutathione oxidase (GSHox)-mimetic activities of AMP@Zn/Mn-MOF can significantly potentiate tumor cell death and effectively induce robust immunogenic cell death (ICD), thereby amplifying the cGAS-STING pathway. Moreover, AMP@Zn/Mn-MOF reprogrammed the immunosuppressive tumor microenvironment by promoting intratumoral lymphocyte infiltration, thereby significantly suppressing the growth of murine MC38 tumors in mice. Notably, AMP@Zn/Mn-MOF amplified the therapeutic effect of anti-programmed death ligand 1 (αPD-L1) blockade by triggering systemic antitumor responses, resulting in a notable abscopal effect to effectively inhibit distant tumors. In summary, AMP@Zn/Mn-MOF offers a nanoplatform with enhanced antitumor effectiveness through activation of the cGAS-STING pathway and ICD, suggesting that enhanced immune checkpoint blockade-based immunotherapy is promising for colon cancer treatment.