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

Area of Science:

• Biomedical Engineering
• Cancer Therapy
• Metabolic Reprogramming

Background:

• Cuproptosis, a regulated cell death pathway, is a potential cancer therapeutic target.
• Non-small cell lung cancer (NSCLC) resists cuproptosis due to high glycolytic activity.

Purpose of the Study:

• To develop a nanoplatform that overcomes NSCLC's intrinsic cuproptosis resistance.
• To investigate the synergistic effects of metabolic reprogramming and copper-induced toxicity in NSCLC.

Main Methods:

• Design of a coordination polymer (Cu-Ox@HA) chelating copper ions with oxamate (Ox) on a hyaluronic acid (HA) template.
• In vitro and in vivo studies utilizing NSCLC models (A549 xenografts).
• Assessment of cuproptosis induction, metabolic pathway alterations, and therapeutic efficacy.

Main Results:

• Cu-Ox@HA releases copper ions and Ox in response to glutathione (GSH), triggering cuproptosis via DLAT oligomerization.
• Oxamate suppresses lactate dehydrogenase A, shifting tumor cell metabolism from glycolysis to oxidative phosphorylation.
• Demonstrated tumor growth inhibition and prolonged survival in vivo, confirming therapeutic potential.

Conclusions:

• The developed nanoplatform effectively reverses cuproptosis resistance in NSCLC through metabolic reprogramming and copper synergy.
• This strategy offers a promising approach for NSCLC treatment by targeting metabolic vulnerabilities.
• Provides mechanistic insights into overcoming drug resistance via metabolic-copper interactions.