PGAM1 Inhibition Promotes HCC Ferroptosis and Synergizes with Anti‐PD‐1 Immunotherapy

• DOI: 10.1002/advs.202301928
• Publication Date: 2023-09-14T13:50:42Z
• Authors: Yimin Zheng; Yining Wang; Zhou Lu; Jinkai Wan; Lulu Jiang; Danjun Song; Chuanyuan Wei; Chao Gao; Guoming Shi; Jian Zhou; Jia Fan; Aiwu Ke; Lu Zhou; Jiabin Cai
• Keywords: Phosphoglycerate Mutase; Carcinoma, Hepatocellular; Science; Q; Liver Neoplasms; hepatocellular carcinoma; CD8-Positive T-Lymphocytes; ferroptosis; 3. Good health; Humans; Ferroptosis; carcinogen metabolism; immunotherapy; Immunotherapy; Research Articles

Abstract The combination of immunotherapy and molecular targeted therapy exhibits promising therapeutic efficacy in hepatocellular carcinoma (HCC), but the underlying mechanism is still unclear. Here, phosphoglycerate mutase 1 (PGAM1) identified as a novel immunometabolic target by using bioinformatic algorithm based on multiple HCC datasets. PGAM1 highly expressed associated with poor prognosis response to immunotherapy. In vitro vivo experiments indicate that targeting inhibited cell growth promoted infiltration CD8 + T‐cells due decreased enzymatic activity. Mechanistically, inhibition promotes ferroptosis downregulating Lipocalin (LCN2) inducing energy stress ROS‐dependent AKT inhibition, which can also downregulate Programmed death 1‐ligand (PD‐L1). Moreover, an allosteric inhibitor (KH3) good antitumor effects patient‐derived xenograft (PDX) models enhanced anti‐PD‐1 subcutaneous orthotopic models. Taken together, findings demonstrate exerts effect promoting T‐cell synergize HCC. Targeting be new strategy “killing two birds one stone” for treatment.