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

Area of Science:

• Biomedical Engineering
• Immunology
• Nanotechnology

Background:

• Molybdenum enzymes and uric acid (UA) are crucial for T-cell activation in anti-tumor immunotherapy.
• Enhancing molybdenum enzyme activity and UA levels can amplify T-cell responses against tumors.

Purpose of the Study:

• To develop a strategy for potentiating anti-tumor immunity by integrating molybdenum-based metalloimmunotherapy with hydrogen sulfide (H2S) gas therapy.
• To investigate the synergistic effects of biodegradable molybdenum sulfide nanoparticles (MoSX NPs) on immune activation and tumor response.

Main Methods:

• Synthesis of biodegradable molybdenum sulfide nanoparticles (MoSX NPs).
• Exploration of MoSX NPs' GSH-responsiveness for controlled release of H2S and molybdate ions (MoO42-).
• Assessment of H2S-mediated mitochondrial damage, mtDNA release, and STING pathway activation.
• Evaluation of MoO42-'s role in cGAS-STING pathway activation and purine metabolic reprogramming.

Main Results:

• MoSX NPs demonstrated efficient GSH-responsiveness, releasing H2S and MoO42-.
• H2S triggered mtDNA release and activated the STING pathway; MoO42- further enhanced cGAS-STING signaling.
• MoO42- modulated purine metabolism, increasing UA levels within tumors.
• The dual-modality approach significantly enhanced anti-tumor immune responses and T-cell activation.

Conclusions:

• Molybdenum-based nanocatalysis offers a promising strategy for metabolic-immune therapy in tumors.
• This approach effectively improves purine metabolic networks and activates T-cells for robust anti-tumor immunity.
• The integration of metalloimmunotherapy and H2S gas therapy via MoSX NPs represents a novel approach to precision cancer treatment.