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Herein, a bimetallic drug\u2010gene co\u2010loading network (Cu\/ZIF\u20108@U\u2010104@siNFS1\u2010HA) is developed that increased the intracellular labile iron pool (LIP) and enhanced the weakly acidic TME by co\u2010suppressing 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, Cu\n                    <jats:sup>2+<\/jats:sup>\n                    is responsively released to deplete glutathione (GSH) and reduce the enzyme activity of glutathione peroxidase 4 (GPX4), achieving the co\u2010inhibition of the three enzymes and further inducing lipid peroxidation (LPO). Additionally, the reactive\u00a0oxygen\u00a0species (ROS) storm in target cells promoted the generation of large numbers of double\u2010stranded DNA breaks. The presence of Zn\n                    <jats:sup>2+<\/jats:sup>\n                    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\u20108@U\u2010104@siNFS1\u2010HA 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.\n                  <\/jats:p>","DOI":"10.1002\/smll.202308397","type":"journal-article","created":{"date-parts":[[2023,12,10]],"date-time":"2023-12-10T21:59:42Z","timestamp":1702245582000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":39,"title":["A Bimetallic Polymerization Network for Effective Increase in Labile Iron Pool and Robust Activation of cGAS\/STING Induces Ferroptosis\u2010Based Tumor Immunotherapy"],"prefix":"10.1002","volume":"20","author":[{"given":"Zhenxin","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Orthopedics The Affiliated Hospital of Xuzhou Medical University  Jiangsu 221002 P. R. 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