Yu Li, Ziyan Song, Jianjun Ding, Yi-Heng Zhou, Tianning Huang, Qufei Qian, Miao Yu, Wenzhao Chen, Jiazheng Liu, Ling Lu, Qiuyang Chen
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.