Tumor microenvironment 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 H 2 S-responsive mesoporous Cu 2 Cl(OH) 3-loading chemotherapeutic cisplatin (CDDP) was synthesized, and the final nanoparticle, CDDP@Cu 2 Cl(OH) 3-CDs (CDCuCDs), was encapsulated by electrostatic action with carbon dots (CDs). CDCuCDs reacted with overproduction H 2 S in colon tumor to produce photothermic copper sulfide for photothermal therapy. CDDP was released by lysis to achieve chemotherapeutic effects. Importantly, CDDP elevated H 2 O 2 levels in cells through a cascade reaction and continuously transforms H 2 O 2 into highly cytotoxic center dot OH through chemodynamic therapy between H 2 O 2 and Cu + , which enables nanoparticles to generate center dot OH and improve the chemotherapeutic efficacy. Highly toxic center dot OH disrupts mitochondrial homeostasis, prohibiting it from performing normal energy-supplying functions. Down-regulated 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 overproduction H 2 S responses in tumors, allowing tumor microenvironment-activated center dot OH nanogenerators to promote tumor energy remodeling for cancer treatment.