Modulating the Electronic Structure of MnNi₂S₃ Nanoelectrodes to Activate Pyroptosis for Electrocatalytic Hydrogen‐Immunotherapy

Hydrogen (H₂) therapy has demonstrated antitumor effect, but the therapeutic efficacy is restricted by the low solubility and nontarget delivery of H₂. Electrolysis of H₂O by electrocatalysts sustainably releases enormous amounts of H₂ and inspires the precise delivery of H₂ for tumor therapy. Herein, manganese-doped Ni₂S₃ nanoelectrodes (MnNi₂S₃ NEs) are designed for the electrocatalytic delivery of H₂ and the activation of antitumor immunity to effectively potentiate H₂-immunotherapy. Ni atoms featuring empty 3d orbitals reduce the initial energy barrier of the hydrogen evolution reaction (HER) by promoting the adsorption of H₂O. Moreover, Mn atoms with different electronegativity modulate the electronic structure of Ni atoms and facilitate the desorption of the generated H₂, thus enhancing the HER activity of the MnNi₂S₃ NEs. Based on the high HER activity, controllable delivery of H₂ for electrocatalytic hydrogen therapy (EHT) is achieved in a voltage-dependent manner. Mechanistically, MnNi₂S₃ NE-mediated EHT induces mitochondrial dysfunction and oxidative stress, which subsequently activates pyroptosis through the typical ROS/caspase-1/GSDMD signaling pathway. Furthermore, MnNi₂S₃ NE-mediated EHT enhances the infiltration of CD8⁺ T lymphocytes into tumors and reverses the immunosuppressive microenvironment. This work demonstrates an electrocatalyst with high HER activity for synergistic gas-immunotherapy, which may spark electrocatalyst-based tumor therapy strategies.