Puerarin Targets MIC19 to Suppress Mitochondrial Metabolism of Tumor‐Infiltrating Tregs and Enhance Anti‐tumor Immunity

Abstract Regulatory T cells (Tregs) are pivotal mediators of immunosuppression in hepatocellular carcinoma, but strategies for selectively disrupting their function remain underdeveloped. Here, puerarin, a natural isoflavone is identifed as a selective immunometabolic modulator. It impairs mitochondrial metabolism in tumor‐infiltrating Tregs (Ti‐Tregs) without affecting conventional T cells. Mechanistically, puerarin directly binds to MIC19—a core subunit of the mitochondrial contact site and cristae organizing system—leading to its degradation and disruption of the MIC19–MIC60 complex. This disruption causes cristae disorganization, reduces oxidative phosphorylation, and weakens the immunosuppressive function of Ti‐Tregs. In vivo, puerarin decreases Ti‐Treg infiltration, thereby enhancing antitumor immunity without causing systemic toxicity. Furthermore, MIC19 knockdown and site‐directed mutagenesis studies validate the role of critical MIC19 residues (His180, Gln187, and Tyr211) in puerarin's activity. These results reveal a mechanism by which puerarin suppresses mitochondrial metabolism of Ti‐Tregs and emphasize the therapeutic potential of natural compounds in metabolic targeting for cancer immunotherapy.