<p>Chemodynamic therapy (CDT) uses the Fenton reaction to generate highly toxic hydroxyl radicals (∙OH) to achieve efficient treatment strategies for tumors. However, the high concentration of glutathione (GSH) in the tumor microenvironment (TME) can scavenge these radicals, thereby diminishing the efficacy of CDT. In this study, we propose a programmable synergistic therapeutic strategy that depletes GSH during chemotherapy (CT) and subsequently increases the production of reactive oxygen species (ROS) to achieve high-potency CDT. We constructed a Cu-Q@Co/ZIF-8 (CQZ) composite nanoplatform by encapsulating cobalt-doped ZIF-8 (Co/ZIF-8) with copper-quercetin (Cu-Q, CQ). The construction of nanoplatform significantly enhanced the water solubility of Co/ZIF-8 and CQ. When the nanoplatform reached the tumor site, the TME triggered the release of quercetin and Cu²⁺ from CQ, thus enabling quercetin-based chemotherapy and Cu²⁺-mediated GSH depletion while generating Cu⁺. Subsequently, the Co²⁺ released from Co/ZIF-8 acted with Cu⁺ to catalyze a Fenton-like reaction with endogenous H₂O₂, efficiently producing toxic ∙OH radicals for CDT. Throughout the treatment process, Cu²⁺ was preferentially released in response to the TME to consume GSH, not only generating Fenton-active Cu⁺ but also preventing the GSH-mediated scavenging of ∙OH. This procedural mechanism has substantially enhanced the therapeutic efficacy of CDT following CT.</p>