Chemodynamic therapy (CDT) has outstanding potential as a combination therapy to treat cancer. However, the effectiveness of CDT in the treatment of solid tumors is limited by the overexpression of glutathione (GSH) in the tumor microenvironment (TME). GSH overexpression diminishes oxidative stress and attenuates chemotherapeutic drug-induced apoptosis in cancer cells. To counter these effects, a synergistic CDT/chemotherapy cancer treatment, involving the use of a multifunctional bioreactor of hollow manganese dioxide (HMnO) loaded with cisplatin (CDDP), was developed. Metal nanoenzymes that can auto-degrade to produce Mn exhibit Fenton-like, GSH-peroxidase-like activity, which effectively depletes GSH in the TME to attenuate the tumor antioxidant capacity. In an acidic environment, Mn catalyzed the decomposition of intra-tumor HO into highly toxic ·OH as a CDT. HMnO with large pores, pore volume, and surface area exhibited a high CDDP loading capacity (>0.6 g). Treatment with CDDP-loaded HMnO increased the intratumor Pt-DNA content, leading to the up-regulation of γ-H2Aχ and an increase in tumor tissue damage. The decreased GSH triggered by HMnO auto-degradation protected Mn-generated ·OH from scavenging to amplify oxidative stress and enhance the efficacy of CDT. The nanoenzymes with encapsulated chemotherapeutic agents deplete GSH and remodel the TME. Thus, tumor CDT/chemotherapy combination therapy is an effective therapeutic strategy.