An allosteric reconfigurable metabzyme hydrogel for adaptive tumor metabolic immunotherapy

Postoperative tumor recurrence remains a major clinical challenge because surgery-induced metabolic dysregulation establishes an immunosuppressive microenvironment characterized by hyperglycemia, lactate accumulation, NADH elevation, and hypoxia. Although catalytic NADH oxidation can directly suppress lactate biogenesis, current NADH oxidase (NOX)-mimetic catalysts are fundamentally limited by rigid catalytic interfaces that hinder efficient electron-relay processes. Here we report an allosteric reconfigurable metabzyme hydrogel for adaptive metabolic-immunotherapy against postoperative recurrence. Inspired by induced-fit enzymatic catalysis, we engineer a manganese-doped molybdenum oxide (Mn-MoO_x) metabzyme featuring a metastable high-entropy lattice that undergoes NADH-triggered interfacial reconstruction, which synchronizes proton-coupled electron transfer (PCET) and accelerates charge flux through cooperative Mn-O-Mo and Mn-O-Mn relay pathways. Combined with raddeanin A, the hydrogel further amplifies oxidative stress, suppresses glycolytic flux and promotes mitochondrial DNA leakage to activate the cGAS-STING pathway. In postoperative models mimicking hostile hyperglycemic and hyperlactatic microenvironments, the hydrogel drives robust antitumor immunity by enforcing a 5.84-fold reduction in lactate and a 5.76-fold enhancement in STING phosphorylation, effectively achieving 94.35% recurrence inhibition and profoundly suppressing metastasis. This work establishes a substrate-responsive allosteric metabzyme that bridges enzymatic plasticity and metallic catalysis, offering a transformative strategy to overcome metabolism-driven immune resistance and achieve durable postoperative tumor control.