A Bimetallic Polymerization Network for Effective Increase in Labile Iron Pool and Robust Activation of cGAS/STING Induces Ferroptosis‐Based Tumor Immunotherapy

Due to the inherent low immunogenicity and immunosuppressive tumor microenvironment (TME) of malignant cancers, the clinical efficacy and application of tumor immunotherapy have been limited. Herein, a bimetallic drug‐gene co‐loading network (Cu/ZIF‐8@U‐104@siNFS1‐HA) is developed that increased the intracellular labile iron pool (LIP) and enhanced the weakly acidic TME by co‐suppressing the dual enzymatic activities of carbonic anhydrase IX (CA IX) and cysteine desulfurylase (NFS1), inducing a safe and efficient initial tumor immunogenic ferroptosis. During this process, Cu2+ is responsively released to deplete glutathione (GSH) and reduce the enzyme activity of glutathione peroxidase 4 (GPX4), achieving the co‐inhibition of the three enzymes and further inducing lipid peroxidation (LPO). Additionally, the reactive oxygen species (ROS) storm in target cells promoted the generation of large numbers of double‐stranded DNA breaks. The presence of Zn2+ substantially increased the expression of cGAS/STING, which cooperated with ferroptosis to strengthen the immunogenic cell death (ICD) response and remodel the immunosuppressive TME. In brief, Cu/ZIF‐8@U‐104@siNFS1‐HA linked ferroptosis with immunotherapy through multiple pathways, including the increase in LIP, regulation of pH, depletion of GSH/GPX4, and activation of STING, effectively inhibiting cancer growth and metastasis. A bimetallic co‐loading network, ZCUNH, is designed as an immunogenic ferroptosis inducer for the treatment of osteosarcoma. This novel inducer can effectively inhibit cancer growth and metastasis by combining ferroptosis with immunotherapy through multiple pathways, including LIP increase, pH regulation, GSH/GPX4 depletion, and cGAS/STING pathway activation.