Copper metal-organic framework-based multifaceted strategy for boosting cancer therapy via synergistic cuproptosis and disulfidptosis.

Cuproptosis, a form of copper-dependent programmed cell death, has emerged as a promising therapeutic target for cancer treatment. However, the efficacy of cuproptosis is undermined by metabolic reprogramming, notably the Warburg effect and the overproduction of glutathione stemming from solute carrier family 7 member 11 (SLC7A11) overexpression. Upregulation of the cystine transporter SLC7A11, while providing a survival advantage, also creates a glucose-dependent metabolic vulnerability in cancer cells, offering a new opportunity for cancer treatment through disulfidptosis under glucose deprivation conditions. Herein, we developed copper-based metal-organic framework nanoparticles, CuSS@876-PEG, which exploit metabolic vulnerabilities by consuming glutathione and subsequently releasing copper ions and the glucose transporter inhibitor BAY-876, thereby eliciting cuproptosis and disulfidptosis. This strategy not only enhances cell death but also stimulates immunogenic cell death, activating the antitumor immune response. To summarize, our innovative strategy provides a multifaceted approach to targeting tumors, paving the way for combined cancer therapy.