Chemodynamic therapy (CDT) based on Fenton-like reaction is often limited by the tumor microenvironment (TME), which has insufficient hydrogen peroxide, and single CDT treatment is often less efficacious. To overcome these limitations, in this study, we designed a hydrogel-based system to enhance the redox stress (EOH) by loading the composite nanomaterial Cu-Hemin-Au, into the agarose hydrogels. The hydrogels could reach the tumor site upon intratumoral injection, and then coagulate and stay for extended period. Once irradiated with near-infrared light, the Cu-Hemin-Au loaded into the EOH acted as a photothermal agent to convert the light energy into heat, and the EOH gradually heated up and softened, releasing the Cu-Hemin-Au residing in it to achieve photothermal therapy (PTT). Benefiting from the glucose oxidase (GOx)-like activity of the Au nanoparticles (NPs), glucose in the tumor cells was largely consumed, and H2 O2 was generated in situ, and then Cu-Hemin-Au reacted with sufficient H2 O2 to generate a large amount of ROS to kill the tumors, which promoted the complete inhibition of tumor growth in mice during the treatment cycle. The hydrogel system for the synergistic enhancement of oxidative stress achieved good PTT/CDT synergy, providing a novel inspiration for the next generation of hydrogels for application in antitumor therapy. This article is protected by copyright. All rights reserved.This article is protected by copyright. All rights reserved.