A Metal Chelation Therapy to Effectively Eliminate Breast Cancer and Intratumor Bacteria While Suppressing Tumor Metastasis by Copper Depletion and Zinc Ions Surge

Abstract The intratumor microbiota results in the immunosuppressive microenvironment and facilitates tumor growth and metastasis. However, developing a synergistic therapy with antitumor, antibacterial, and antimetastatic effects faces enormous challenges. Here, we propose an innovative metal chelation therapy to effectively eliminate tumor and intratumor bacteria and suppress tumor metastasis. Different from traditional chelation therapy that only consumes metal elements, this therapy not only eliminates the crucial metal elements for tumor metabolism but also releases new metal ions with antitumor and antibacterial properties. Based on the high demand for copper in breast cancer, we prepare a fibrous therapeutic nanoagent (Zn‐PEN) by chelating the copper chelator D‐Penicillamine (D‐PEN) with Zn 2+ . Firstly, Zn‐PEN achieves dual inhibition of oxidative phosphorylation (OXPHOS) and glycolysis metabolism in breast cancer through copper depletion and Zn 2+ activated cGAS‐STING pathway, thus inducing tumor cell death. Secondly, Zn‐PEN has the capability to eradicate Fusobacterium nucleatum ( F. nucleatum ) in breast cancer, thereby mitigating its immunosuppressive impact on the tumor microenvironment. Finally, Zn‐PEN effectively inhibits tumor metastasis through multiple routes, including the inhibition of epithelial‐mesenchymal transition (EMT) process, activation of cGAS‐STING pathway, and elimination with F. nucleatum . Therefore, we verify the feasibility of Zn‐PEN mediated metal chelation therapy in a 4T1 model infected with F. nucleatum , providing a new therapeutic strategy for inhibiting tumor metastasis.