Manganese Galvanic Cells Intervene in Tumor Metabolism to Reinforce cGAS‐STING Activation for Bidirectional Synergistic Hydrogen‐Immunotherapy

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.