Therapeutic nanosystems triggered by a specific tumor microenvironment (TME) offer excellent safety and selectivity in the treatment of cancer by in situ conversion of a less toxic substance into effective anticarcinogens. However, the inherent antioxidant systems, hypoxic environment, and insufficient hydrogen peroxide (H₂O₂) in tumor cells severely limit their efficacy. Herein, a new strategy has been developed by loading the chemotherapy prodrug disulfiram (DSF) and coating glucose oxidase (GOD) on the surface of Cu/ZIF-8 nanospheres and finally encapsulating manganese dioxide (MnO₂) nanoshells to achieve efficient DSF-based cancer chemotherapy and dual-enhanced chemodynamic therapy (CDT). In an acidic TME, the nanocatalyst can biodegrade rapidly and accelerate the release of internal active substances. The outer layer of MnO₂ depletes glutathione (GSH) to destroy the reactive oxygen defensive mechanisms and achieves continuous oxygen generation, thus enhancing the catalytic efficiency of GOD to burst H₂O₂. Benefiting from the chelation reaction between the released Cu²⁺ and DSF, a large amount of cytotoxic CuET products is generated, and the Cu⁺ are concurrently released, thereby achieving efficient chemotherapy and satisfactory CDT efficacy. Furthermore, the release of Mn²⁺ can initiate magnetic resonance imaging signals for the tracking of the nanocatalyst.