Lactate‐Modulating Nanozyme‐Mediated Mitochondrial Respiration Block for Tumor Immunosuppression Remodeling

Abnormal lactate metabolism in tumor cells leads to immune escape in the tumor microenvironment. Intervening in specific lactate metabolic pathways while blocking downstream pyruvate influx holds great promise for overcoming conventional lactate-targeted therapy limitations such as short half-life, insufficient lactate consumption, and pathological microenvironment elasticity. Herein, a nanocatalytic medicine based on carbondoping engineered copper nitride enzyme (Cu₃N-C NE) with enhanced lactate oxidase (LOX) activity was carefully designed. Computational results revealed that the introduction of C favors activation of the hydroxyalkyl C-H bond in lactate by the polarization of adjacent hydroxyl groups, correspondingly facilitating the abstraction of hydrogen atoms from the desired α-C-H and α-C-O-H groups in lactate via the hydrogen atom-transfer (HAT) process. The Cu₃N-C NEs could downregulate lactate levels in tumor cells for robust remodeling of the immunosuppressive microenvironment and further block as-generated pyruvate to influx into the mitochondrial respiration, achieving lactate homeostasis reprogramming. Our study provides a proof-of-concept design of next-generation lactate-modulation nanomedicine via heteroatom-doping and evolution with the additional potential to expedite the industrial production of lactate to pyruvate.