Copper-Oxamate Coordination Polymers Reverse Cuproptosis Resistance in Nonsmall Cell Lung Cancer via Glycolysis Reprogramming

Cuproptosis, a recently identified regulated cell death pathway, is emerging as a promising therapeutic target for cancer. However, nonsmall cell lung cancer (NSCLC) exhibits inherent resistance to copper-induced toxicity, which is primarily due to enhanced glycolytic activity. Herein, a coordination polymer (Cu-Ox@HA) is designed by the chelation of copper ions with the glycolysis inhibitor oxamate (Ox), using hyaluronic acid (HA) as a biocompatible template. In the tumor microenvironment, Cu-Ox@HA disassembles in response to glutathione (GSH), enabling the synchronous release of copper ions and Ox. GSH depletion facilitates the reduction of Cu(II) to Cu(I), which exhibits high binding affinity to lipoylated dihydrolipoamide S-acetyltransferase (DLAT) and thereby triggers DLAT oligomerization and subsequent cuproptosis. Meanwhile, the released Ox suppresses lactate dehydrogenase A, which blocks the pyruvate-to-lactate conversion in the glycolytic pathway and disrupts tumor cell energy metabolism. Thus, this nanoplatform promotes the cuproptosis response of NSCLC by glycolytic reprogramming. Both in vitro and in vivo results demonstrate that metabolic reprogramming converts tumor cells' metabolism from glycolysis to oxidative phosphorylation and overcomes intrinsic cuproptosis resistance. Moreover, in vivo studies using A549 xenograft models confirm tumor growth inhibition and prolonged survival of treated mice, verifying the therapeutic potential of this strategy. Overall, this work presents a nanomedicine approach for reversing cuproptosis resistance through metabolic-copper synergy, providing mechanistic insights for NSCLC treatment.