Copper ion (Cu2+) has been revealed to be involved in the occurrence and development of oral squamous cell carcinoma (OSCC), making copper-mediated chemodynamic therapy (Cu-CDT) a promising treatment strategy for OSCC by elevating Cu2+ levels to generating a large amount of reactive oxygen species (ROS). However, the excessive reduced glutathione (GSH) in the tumor microenvironment can scavenge the ROS generated by Cu-CDT. While the directional co-delivery of Cu2+ and GSH-depleting agents shows promise for Cu-CDT in OSCC therapy, their rapid metabolism and the superficial nature of OSCC lesions necessitate tailored drug formulations to ensure effective bioavailability. To counteract this challenge, this work proposed a practical hydrogel-supported ROS-GSH regulation strategy, which involves the on-demand design of a copper ion-crosslinked guanosine-based hydrogel (GCD) containing dimethyl fumarate (DMF, which conjugates with GSH for consumption). It can directionally and sustainably co-deliver Cu2+ and DMF to OSCC lesions under mildly acidic pH conditions, thereby enhancing Cu-CDT efficiency through improved Cu2+ utilization and DMF-driven GSH depletion. As anticipated, the strategy sustains the generation of hydroxyl radicals, effectively inducing apoptosis and suppressing cell proliferation in CAL-27 cells, which consequently inhibits the growth of OSCC tumors. Therefore, this work highlights the GCD hydrogel's great potential as a promising Cu-CDT therapeutic platform.Copyright © 2025. Published by Elsevier B.V.