An Integrated Therapeutic Strategy to Enhance Cuproptosis through Adaptive Activation and Microenvironment Remodeling of Prodrug Complexes

Colorectal cancer remains a significant health threat, with current treatment options facing numerous limitations. Cuproptosis, a novel copper-dependent form of programmed cell death, has garnered widespread attention. This mechanism triggers apoptosis and activates immunity by disrupting mitochondrial function through the accumulation of copper ions. However, the tumor microenvironment (TME) of CRC is rich in endogenous hydrogen sulfide (H ₂ S), which stabilizes relevant proteins and alleviates the oxidative stress induced by Cuproptosis. To overcome this challenge, we propose a TME-adaptive dual prodrug strategy. It reshapes the TME to reverse the protective effects of H₂S against cuproptosis, while on the other, it integrates chemotherapy and photothermal therapy to amplify copper death and mitochondrial damage, thereby enhancing therapeutic efficacy. This strategy adapts to activate dual prodrugs, with the synergistic effects between the drugs enhancing the therapeutic outcome, providing a multi-modal approach for enhanced efficacy.