2025 · Yang — Manganese Galvanic Cells Intervene in Tumor Metabolism to Reinforce cGAS-STING Activation for Bidirectional Synergistic Hydrogen-Immunotherapy.
Super-Abstract
Manganese galvanic-cell nanostructures (MnG) generate hydrogen and manganese ions inside tumours by reacting with water, simultaneously activating a key innate-immunity pathway (cGAS-STING) and disrupting tumour glucose metabolism. In animal models, MnG combined with immune checkpoint blockade suppressed both injected primary tumours and distant untreated tumours — and showed remarkable efficacy in a rabbit liver tumour model combined with transarterial embolisation. (Advanced Materials, 2025.)
Commentary
This is a preclinical animal study. The cGAS-STING pathway is a critical sensor of cytosolic DNA that triggers innate and adaptive immunity — a highly relevant target in cancer immunotherapy. The MnG approach is mechanistically layered: Mn²⁺ ions amplify cGAS-STING signalling directly, while simultaneously suppressing glycolysis (specifically TREX2 expression), which would otherwise dampen cGAS-STING activation. H₂ generation serves as the effector arm of tumour metabolic disruption. The addition of a transarterial embolisation model (using MnG in lipiodol) shows potential for interventional oncology. However, all efficacy data are from mouse and rabbit models, and the Mn²⁺ safety profile at therapeutic doses in humans is not yet established.
Key quotes
- „MnG not only activated and amplified the cGAS-STING pathway through the sustained release of Mn2+ but also regulated tumor glucose metabolism to inhibit the expression of three prime repair exonuclease 2 (TREX2), thereby synergistically enhancing the activation of the cGAS-STING pathway.“ — dual mechanism: Mn²⁺ directly activates cGAS-STING + suppresses its inhibitor TREX2 via metabolic reprogramming
- „The combination of MnG with immune checkpoint blockade therapy resulted in significant suppression of both primary tumors and distant tumors.“ — abscopal-like systemic immune effect observed in mice
- „The MnG-lipiodol dispersion exhibited remarkable efficacy in combination with transarterial embolization (TAE)-gas-immunotherapy in a rabbit orthotopic liver tumor model.“ — potential for interventional radiology / liver cancer application
Our assessment
This is a preclinical animal study (mouse + rabbit) — results cannot be directly transferred to humans. The bidirectional cGAS-STING amplification strategy is mechanistically compelling and well-supported by the data presented. The combination with TAE is a clinically realistic administration route for liver tumours. Translational barriers include Mn²⁺ neurotoxicity at higher doses, nanoparticle biodistribution and immune-related toxicity, and the complexity of combining multiple immune-activating agents. No human data exist.
Study design
- Type: preclinical animal study · Models: mouse subcutaneous/bilateral tumour models; rabbit orthotopic liver tumour model · H₂ delivery: water etching of MnG nanostructures → in-situ H₂ + Mn²⁺ release
- Endpoints: primary and distant tumour volume, immune cell profiling (dendritic cells, T cells, macrophages), cGAS-STING pathway markers, TREX2 expression, glycolysis metrics · Result: significant tumour suppression; systemic immune activation; synergy with anti-PD-L1; efficacy in TAE-combined liver model
Abstract
The cGAS-STING pathway is pivotal in initiating antitumor immunity. However, tumor metabolism, particularly glycolysis, negatively regulates the activation of the cGAS-STING pathway. Herein, Mn galvanic cells (MnG) are prepared via liquid-phase exfoliation and in situ galvanic replacement to modulate tumor metabolism, thereby enhancing cGAS-STING activation for bidirectional synergistic H2-immunotherapy. The obtained MnG can be etched by water, enabling efficient and sustained generation of H2 gas and Mn2+. MnG not only activated and amplified the cGAS-STING pathway through the sustained release of Mn2+ but also regulated tumor glucose metabolism to inhibit the expression of three prime repair exonuclease 2 (TREX2), thereby synergistically enhancing the activation of the cGAS-STING pathway. The injection of MnG into tumors resulted in a robust immune response, thereby providing favorable support for antitumor therapy. Consequently, the combination of MnG with immune checkpoint blockade therapy resulted in significant suppression of both primary tumors and distant tumors. Furthermore, the MnG-lipiodol dispersion exhibited remarkable efficacy in combination with transarterial embolization (TAE)-gas-immunotherapy in a rabbit orthotopic liver tumor model. The present study underscores the significance of employing a metal galvanic cell strategy for enhanced immunotherapy, thereby offering a novel approach for rational design of bioactive materials to augment immunotherapeutic effectiveness.
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