Engineering‐Modulated Molybdenum Enzymes Strategy for Tumor‐Specific Metabolic‐Immunotherapy

ABSTRACT Molybdenum enzymes and one of their catalytic products, uric acid (UA), play important roles in T‐cell activation; thereby, enhancing molybdenum enzyme activity and increasing UA levels within tumors can further activate T‐cell and enhance anti‐tumor immunotherapy. To achieve this goal, biodegradable molybdenum sulfide nanoparticles (MoS X NPs) were synthesized to increase molybdenum enzyme activity and thus effectively potentiate anti‐tumor immunity by integrating molybdenum‐based metalloimmunotherapy with hydrogen sulfide (H 2 S) gas therapy. This dual‐modality approach not only amplified immune activation but also triggered the stimulator of interferon genes (STING) signaling pathway and modulated purine metabolic networks, thereby orchestrating a comprehensive enhancement of anti‐tumor immune responses. In detail, the biodegradable MoS X NPs exhibited excellent GSH‐responsiveness, triggering the rapid release of H 2 S and molybdate ions (MoO 4 2− ). H 2 S‐mediated mitochondrial damage elicited the release of mitochondrial DNA (mtDNA), which activated the STING pathway, while MoO 4 2− further enhanced the activation of the cGAS‐STING signaling pathway. As the catalytic moiety of molybdenum, MoO 4 2− regulated cellular purine metabolic reprogramming and increased UA level with the tumor, thereby achieving synergistic anti‐tumor immune responses. This study proposes a molybdenum‐based nanocatalytic strategy to improve purine metabolic networks, activate T‐cell, and trigger a strong anti‐tumor response, thereby achieving precision metabolic‐immune therapy for tumors.