Xie Yulin, Wang Junrong, Li Lei, Wang Man, Sun Jikai, Chang Jiaying, Lin Jun, Li Chunxia
Institute of Frontier Chemistry, School of Chemistry and Chemical Engineering, Shandong University, Qingdao, 266237, P. R. China.
State Key Laboratory of Rare Earth Resource Utilization Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, 130022, P. R. China.
Angew Chem Int Ed Engl. 2025 Jan 27;64(5):e202417592. doi: 10.1002/anie.202417592. Epub 2024 Nov 11.
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. Firstly, Zn-PEN achieves dual inhibition of oxidative phosphorylation (OXPHOS) and glycolysis metabolism in breast cancer through copper depletion and Zn 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.
肿瘤内微生物群导致免疫抑制微环境，促进肿瘤生长和转移。然而，开发一种具有抗肿瘤、抗菌和抗转移作用的协同疗法面临巨大挑战。在此，我们提出一种创新的金属螯合疗法，以有效消除肿瘤和肿瘤内细菌并抑制肿瘤转移。与仅消耗金属元素的传统螯合疗法不同，这种疗法不仅消除了肿瘤代谢所需的关键金属元素，还释放出具有抗肿瘤和抗菌特性的新金属离子。基于乳腺癌对铜的高需求，我们通过将铜螯合剂D-青霉胺（D-PEN）与锌螯合制备了一种纤维状治疗纳米剂（Zn-PEN）。首先，Zn-PEN通过消耗铜和激活锌介导的cGAS-STING途径实现对乳腺癌氧化磷酸化（OXPHOS）和糖酵解代谢的双重抑制，从而诱导肿瘤细胞死亡。其次，Zn-PEN有能力根除乳腺癌中的具核梭杆菌（F. nucleatum），从而减轻其对肿瘤微环境的免疫抑制影响。最后，Zn-PEN通过多种途径有效抑制肿瘤转移，包括抑制上皮-间质转化（EMT）过程、激活cGAS-STING途径以及消除具核梭杆菌。因此，我们在感染具核梭杆菌的4T1模型中验证了Zn-PEN介导的金属螯合疗法的可行性，为抑制肿瘤转移提供了一种新的治疗策略。
