Introduction:Lung cancer the most prevalent cause of cancer-related deaths, and current therapies lack sufficient specificity and efficacy. This study developed an injectable thermosensitive hydrogel harboring hollow copper sulfide nanoparticles and β-lapachone (Lap) (CLH) for lung tumor treatment.Methods:The hydrogel-encapsulated CLH system can remotely control the release of copper ions (Cu2+) and drugs using photothermal effects for non-invasive controlled-release drug delivery in tumor therapy. The released Cu2+consumes the overexpressed GSH in TME and the generated Cu+further exploits the TME characteristics to initiate nanocatalytic reactions for generating highly toxic hydroxyl radicals. In addition, in cancer cells overexpressing Nicotinamide adenine dinucleotide (phosphate): quinone oxidoreductase 1 (NQO1), Lap can catalyze the generation of hydrogen peroxide (H2O2) through futile redox cycles. H2O2is further converted into highly toxic hydroxyl radicals via the Fenton-like reaction, leading to a burst of reactive oxygen species in TME, which further enhances the therapeutic effect of chemokines.Results:Analysis of the antitumor efficacy in a subcutaneous A549 lung tumor model mice showed a significant delay in tumor growth and no systemic toxicity was detected.Discussion:In conclusion, we have established a CLH nanodrug platform that enables efficient lung tumor therapy through combined photothermal/chemodynamic therapy (CDT) treatment and self-supplying H2O2to achieve cascade catalysis, leading to explosive amplification of oxidative stress.