Chemodynamic therapy (CDT) can kill cancer cells by generating toxic agents within tumors through Fenton-/Fenton-like reaction, exhibiting high tumor specificity and low systemic toxicity. However, the therapeutic effect of CDT is usually limited by the overexpressed glutathione (GSH) and low catalytic efficiency in the tumor microenvironment. To deplete GSH and achieve chemo/photothermal/chemodynamic combination therapy, Cu²⁺, the photothermal material polydopamine (PDA), and chemotherapeutic agent DOX were used to construct a copper-doped MOF-based nanocomposite (DOX@Cu²⁺/ZIF-8@PDA, DCZP). The Cu²⁺ could be reduced to Cu⁺ by GSH to achieve GSH depletion and CDT activation. Under laser irradiation, the heat generated by DCZP could be used for photothermal therapy and promote the Fenton-like reaction with the released DOX to achieve combination therapy. Extracellular experiments demonstrated that more than 50% of GSH could be consumed and the generated heat upon laser irradiation could promote •OH production. In vitro experiments showed that the DCZP combined therapy resulted in 49.4% of late cell apoptosis. More importantly, under the combination therapy of DCZP, the tumors of mice were almost ablated and the expression of tumor growth factors also could be suppressed. The work provided a promising strategy by constructing a GSH depletion and combination therapy nanocomposite for safe and efficient cancer therapy.