Combating oxidative stress resistance in copper-mediated chemodynamic therapy through redox metabolism regulation

Redox metabolism in tumor cells is considered a vulnerable target for cancer therapy. Benefiting from the elevated copper-ion levels characteristic of tumorigenesis and progression, copper-mediated chemodynamic therapy (Cu-CDT) demonstrates remarkable efficacy in inducing oxidative stress-mediated cancer cell death. However, Cu-CDT encounters challenges related to the inherently low hydrogen peroxide (H₂O₂) level and the high glutathione (GSH) level in cancer cells to counteract oxidative stress-mediated therapeutic efficacy. Although strategies for elevating H₂O₂ levels, depleting GSH levels, and synergizing with other tumor therapies to enhance Cu-CDT have been increasingly reported, their underlying redox metabolism mechanisms have yet to be systematically summarized and thoroughly elucidated. In this regard, the latest progress in combating oxidative stress resistance in Cu-CDT through redox metabolism regulation has been comprehensively reviewed following the "chemical principles-biological mechanisms-regulatory approaches" logical flow. Firstly, the opportunity for Cu-CDT in tumor therapy and the related GSH-mediated oxidative stress resistance mechanism was discussed. Secondly, the existing redox metabolism regulation via H₂O₂ elevation and GSH depletion in Cu-CDT were classified. Thirdly, the underlying biological regulation mechanisms along the molecular route of "stress response-execution pathway-cell death" were elucidated. Fourthly, mechanism-modulated and engineered delivery strategies for enhancing Cu-CDT through redox metabolism regulation were further proposed. Finally, several foreseeable challenges and opportunities for advancing Cu-CDT were outlined. Generally, this review seeks to provide novel perspectives on enhancing the Cu-CDT therapeutic efficacy, with the broader aspiration of contributing to its future bench-to-bedside research.