Engineering-Modulated Molybdenum Enzymes Strategy for Tumor-Specific Metabolic-Immunotherapy.

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 (MoSX NPs) were synthesized to increase molybdenum enzyme activity and thus effectively potentiate anti-tumor immunity by integrating molybdenum-based metalloimmunotherapy with hydrogen sulfide (H2S) 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 MoSX NPs exhibited excellent GSH-responsiveness, triggering the rapid release of H2S and molybdate ions (MoO4 2-). H2S-mediated mitochondrial damage elicited the release of mitochondrial DNA (mtDNA), which activated the STING pathway, while MoO4 2- further enhanced the activation of the cGAS-STING signaling pathway. As the catalytic moiety of molybdenum, MoO4 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.