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

Abstract Hydrogen (H 2 ) therapy has demonstrated antitumor effect, but the therapeutic efficacy is restricted by the low solubility and nontarget delivery of H 2 . Electrolysis of H 2 O by electrocatalysts sustainably releases enormous amounts of H 2 and inspires the precise delivery of H 2 for tumor therapy. Herein, manganese‐doped Ni 2 S 3 nanoelectrodes (MnNi 2 S 3 NEs) are designed for the electrocatalytic delivery of H 2 and the activation of antitumor immunity to effectively potentiate H 2 ‐immunotherapy. Ni atoms featuring empty 3d orbitals reduce the initial energy barrier of the hydrogen evolution reaction (HER) by promoting the adsorption of H 2 O. Moreover, Mn atoms with different electronegativity modulate the electronic structure of Ni atoms and facilitate the desorption of the generated H 2 , thus enhancing the HER activity of the MnNi 2 S 3 NEs. Based on the high HER activity, controllable delivery of H 2 for electrocatalytic hydrogen therapy (EHT) is achieved in a voltage‐dependent manner. Mechanistically, MnNi 2 S 3 NE‐mediated EHT induces mitochondrial dysfunction and oxidative stress, which subsequently activates pyroptosis through the typical ROS/caspase‐1/GSDMD signaling pathway. Furthermore, MnNi 2 S 3 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.