A Self−Augmenting Strategy of Glucose Starvation to Trigger Disulfidptosis for Enhanced Cancer Immunotherapy

ABSTRACT Glucose oxidase (GOx)−based therapy has emerged as a promising strategy for cancer treatment, yet its efficacy is constrained by limited active sites and suboptimal reaction kinetics. To address these challenges, we designed a ruthenium (Ru)–rhodium (Rh) alloy anchored on layered double hydroxide (denoted as RuRh@LDH) as an advanced nanozyme that concurrently mimics GOx‐ and catalase (CAT)−like activities. Unlike the traditional enzyme process, this RuRh@LDH initiates an alternative pathway by self−propelling catalytic cascade, where the O 2 produced by the CAT−like reaction directly fuels the GOx−like process, establishing an autocatalytic cycle that significantly enhances reaction kinetics, which was verified by the Density Functional Theory (DFT) calculations. As a result, RuRh@LDH exhibits exceptional catalytic efficiency attributable to the synergistic electronic interaction within the alloy structure and the dual heat and mass transfer pathways between adjacent catalytic sites. The self−sustaining reaction leads to rapid glucose depletion, disrupting both energy metabolism and redox homeostasis, and ultimately triggering disulfidptosis. Finally, RuRh@LDH suppressed tumor growth and promoted T cell infiltration, showing potent antitumor and immune‐activating effects. This work establishes a self‐accelerating alloy nanozyme, representing a paradigm shift in enzyme‐mimetic therapy for sustainable metabolic intervention in cancer.