Reactive oxygen species (ROS)-mediated antitumor modalities that induced oxidative damage of cancer cells have recently acquired increasing attention on account of their noninvasiveness, low systemic toxicity, and high specificity. However, their clinical efficacy was often constrained by complex and various tumor microenvironment (TME), especially hypoxia characteristic and antioxidation effect of glutathione (GSH). Herein, we constructed a multinanozyme system based on hyaluronic acid (HA)-stabilized CuMnOx nanoparticles (CMOH) loaded with indocyanine green (ICG) with high-efficient ROS generation, O2 self-evolving function, GSH depletion ability and hyperthermia effect for achieving hypoxic tumor therapy. The CMOH nanozymes exhibited peroxidase-like and oxidase-like activities, which could efficiently catalyze H2O2 or O2 to generate hydroxyl radicals (•OH) or superoxide radicals (•O2-) in acidic tumor microenvironment (TME), elevating oxidative stress of tumor. Indocyanine green (ICG) was further loaded into HA-CuMnOx to form HA-CuMnOx@ICG nanocomposites (CMOI NCs), which can effectively generate singlet oxygen (1O2) and local hyperthermia under light irradiation. The hyperthermia generated by CMOI NCs further enhances the catalytic activities of nanozymes for ROS generation. Meanwhile, the CMOI with catalase-like activity could catalyze H2O2 into O2 for relieving tumor hypoxia and elevate O2-dependent ROS generation. Notably, CMOI can consume endogenous GSH, thereby impairing tumor antioxidant system and enhancing ROS-based therapy efficacy. After modified with HA, CMOI NCs with tumor targeting ability realized synergistic PTT-enhanced tumor oxidation therapy based on their multimodal properties. Thus, this work contributes to design high-performance therapeutic reagent to overcome the limitation of hypoxia and high antioxidant defense of tumor. STATEMENT OF SIGNIFICANCE: Reactive oxygen species (ROS)-mediated antitumor modalities were often constrained by complex and various tumor microenvironment (TME), especially hypoxia characteristic and antioxidation effect of glutathione (GSH). In this work, a multinanozyme system based on hyaluronic acid (HA)-stabilized CuMnOx nanoparticles (CMOH) loaded with indocyanine green (ICG) was designed to realize PTT-enhanced multiple catalysis tumor therapy. Although antitumor modalities based on multienzyme catalysis have been developed. Here, we highlighted the responsive catalysis of multienzyme system on tumor microenvironment (TME) and the promoting effect of photothermal effect on ROS production. Both in vitro and in vivo manifested that the enhanced anticancer efficacy of CMOI NCs due to their thermally amplified catalytic activity and TME regulation ability.