Recently, Prof. Li Chunxia’s group at Institute of Frontier Chemistry, School of Chemistry and Chemical Engineering, Shandong University, has achieved a series of new advances in inhibiting tumor metastasis by metal chelation therapy. The research titled “EDTA-Mg Nano-Chelators Amplify Ferroptosis by Artificially Simulating the Epithelial-Mesenchymal Transition Process and Endogenous Iron Deprivation” was published in Angewandte Chemie International Edition and was selected as a “Hot Paper”. Prof. Li Chunxia and Prof. Gao Haidong (Qilu Hospital, Qingdao) are the co-corresponding authors, while Xie Yulin and Jiang Tengfei are the co-first authors. Additionally, another research titled “Antagonistic Iron Competition Induced by Iron Chelators Heightens Cuproptosis in Both Tumors and Intratumoral Bacteria” was published in the Advanced Materials. Prof. Li Chunxia is the sole corresponding author, and Xie Yulin is the first author.

Prof. Li’s group has long been exploring strategies to enhance antitumor immunotherapy and inhibit tumor metastasis, and has recently reported a series of new breakthroughs. Traditional chelation therapy often requires strict dosage control and continuous patient monitoring due to its lack of specificity and targeting. To overcome this limitation, the group proposed a novel metal chelation therapy that uses metal ions with weak chelating ability coordinated with chelating agents to construct nano-chelators that accumulate in the tumor site (Angew. Chem. Int. Ed. 2025, 64, e202417592). This approach depletes metal ions essential for tumor growth while releasing cytotoxic metal ions. This nano-engineering strategy not only improves the selectivity of chelators for specific metal ions but also enhances their long-term accumulation at the tumor site. Building on this, the group further designed two therapeutic strategies centered on metal chelation therapy, targeting the epithelial-mesenchymal transition (EMT) process and intratumoral microbiota, aiming to break the immunosuppressive tumor microenvironment and effectively inhibit tumor metastasis.

(1)EDTA‑Mg nano‑chelators amplify ferroptosis via EMT simulation and iron deprivation.

EMT is a key step in initiating tumor metastasis. Commonly, researchers focus on inhibiting EMT to prevent tumor metastasis. However, they ignore that tumor cells undergoing EMT are more vulnerable to disturbance from the external environment. Tumor cells in this period are a potential therapeutic target, yet precisely regulating the EMT of tumor cells remains a challenging problem to be solved. Here, based on metal chelation therapy, Prof. Li’s group proposes a strategy of artificially mimicking EMT, integrating ferroptosis and immunotherapy to inhibit tumor growth and metastasis. The prepared ethylene diamine tetraacetic acid-magnesium (EDTA-Mg). On the one hand, chelates Ca²⁺on the surface of tumor cells to form EDTA-Ca, causing the dissociation of tumor cells. Meanwhile, E-cadherin is downregulated, while Vimentin and matrix metalloproteinase 2 (MMP-2) are upregulated, indicating the occurrence of EMT. On the other hand, after EDTA-Ca is endocytosed by tumor cells, it deprives Fe in the lysosomes to form EDTA-Fe, which induces ferroptosis through a Fenton reaction. Ferroptosis, combined with the initially released Mg²⁺, synergistically amplifies the immune response, thereby inhibiting tumor metastasis（Angew. Chem. Int. Ed.2025, 64, e202506126, Hot Paper）.

Figure 1. Schematic diagram of EDTA-Mg preparation and its mechanism for tumor suppression.

(2)Iron chelators induce cuproptosis in tumors and bacteria via antagonistic iron competition.

Both tumors and intratumoral bacteria exhibit iron addiction, a shared metabolic dependency that drives their proliferation. Here, inspired by the ancient Chinese fable “The Snipe and the Clam Grapple While the Fisherman Profits”, a nano-chelator, copper-deferiprone (Cu-DFP), is designed and synthesized to deplete iron ions by metal chelation therapy in the tumor microenvironment, thereby “sowing discord” between tumors and intratumoral bacteria and subsequently inducing cuproptosis in both (Figure 2). Specifically, capitalizing on the high iron stores in both tumor cells and intratumoral bacteria, coupled with the superior iron-chelating capability of DFP, Cu-DFP effectively hijacks iron ions from these cellular reservoirs while concurrently liberating substantial amounts of copper ions (Cu²⁺). Iron depletion not only exacerbates the antagonistic rivalry between tumors and bacteria but also disrupts their defense mechanisms against external stressors. Moreover, the released Cu²⁺ leads to excessive intracellular copper accumulation, triggering cuproptosis in both. The dying tumor cells and bacteria then release damage-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs), respectively, promoting dendritic cells (DCs) maturation and activating antitumor immune responses. By harnessing the iron-mediated metabolic competition to potentiate cuproptosis, this therapeutic strategy presents an innovative method for addressing intratumoral microbiota in oncology（Adv. Mater. 2026, 38, e15904）.

Figure 2. Schematic diagram of the synergistic antitumor and antibacterial effects of Cu-DFP through iron deprivation and cuproptosis.

The above research outcomes expand the therapeutic strategies for inhibiting tumor metastasis and lay a solid foundation for a deeper understanding of the metastatic process. Moreover, the metal chelation therapy proposed by Prof. Li’s group is not only applicable to breast cancer but also holds potential value for treating other types of cancer. This work was supported by the National Natural Science Foundation of China and the Qingdao Science and Technology Benefiting the People Demonstration Project.

The linking for papers：https://onlinelibrary.wiley.com/doi/full/10.1002/anie.202506126

https://advanced.onlinelibrary.wiley.com/doi/full/10.1002/adma.202515904

[Contributed by Institute of Frontier Chemistry, School of Chemistry and Chemical Engineering. Author: Xie Yulin]