H <sub>2</sub>S and Cisplatin Activation Amplify Oxidative Stress Promoting Tumor Energy Remodeling for Mild Photothermal Therapy and Cuproptosis

Tumor metabolic reprogramming requires high levels of adenosine triphosphate (ATP) to maintain treatment resistance, which poses major challenges to chemotherapy and photothermal therapy. Especially, high levels of ATP promote copper ion efflux for limiting the curative effect of cuproptosis. Here, an H2S-responsive mesoporous Cu2Cl(OH)3-loading chemotherapeutic cisplatin (Pt) was synthesized, and the final nanoparticle, Pt@Cu2Cl(OH)3-CDs (PtCuCDs), was encapsulated by electrostatic action with carbon dots. PtCuCDs reacted with overexpressed H2S in colon tumor to produce photothermic copper sulfide for photothermal therapy. Pt was released by lysis to confer chemotherapeutic effects. Importantly, Pt elevated H2O2 levels in cells through a cascade reaction and continuously transforms H2O2 into highly cytotoxic •OH through chemodynamic therapy between H2O2 and Cu+, which enables nanoparticles to generate •OH and improve the chemotherapeutic efficacy. Highly toxic •OH disrupts mitochondrial homeostasis, prohibiting it from performing normal energy-supplying functions. Downregulated ATP inhibits heat shock protein expression, which promotes the therapeutic effect of mild photothermal therapy and reduces the efflux of intracellular copper ions, thus improving the therapeutic effect of cuproptosis. Our research provides a potential therapeutic strategy using overexpressed H2S responses in tumors, allowing tumor microenvironment-activated •OH nanogenerators to promote tumor energy remodeling for cancer treatment.