Manganese-Based Immunostimulatory Metal–Organic Framework Activates the cGAS-STING Pathway for Cancer Metalloimmunotherapy

Metal-organic frameworks (MOFs) show tremendous promise for drug delivery due to their structural and functional versatility. However, MOFs are usually used as biologically inert carriers in most cases. The creation of intrinsically immunostimulatory MOFs remains challenging. In this study, a facile and green synthesis method is proposed for the preparation of a manganese ion (Mn²⁺)-based immunostimulatory MOF (ISAMn-MOF) for cancer metalloimmunotherapy. ISAMn-MOF significantly facilitates the activation of cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) related genes and signaling pathways in bone-marrow-derived dendritic cells (BMDCs). BMDCs treated with ISAMn-MOF secrete 4-fold higher type I interferon and 2- to 16-fold higher proinflammatory cytokines than those treated with equivalent MnCl₂. ISAMn-MOF alone or its combination with immune checkpoint antibodies significantly suppresses tumor growth and metastasis and prolongs mouse survival. Mechanistic studies indicate that ISAMn-MOF treatment facilitates the infiltration of stimulatory immune cells in tumors and lymphoid organs. This study provides insight into the design of bioactive MOFs for improved cancer metalloimmunotherapy.