Antagonistic Iron Competition Induced by Iron Chelators Heightens Cuproptosis in Both Tumors and Intratumoral Bacteria

Abstract

Abstract 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. 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 (Cu 2+ ). Iron depletion not only exacerbates the antagonistic rivalry between tumors and bacteria but also disrupts their defense mechanisms against external stressors. Moreover, the released Cu 2+ 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.