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

• Published in: Advanced science Vol. 10; no. 29; pp. e2301928 - n/a
• Main Authors: Zheng, Yimin, Wang, Yining, Lu, Zhou, Wan, Jinkai, Jiang, Lulu, Song, Danjun, Wei, Chuanyuan, Gao, Chao, Shi, Guoming, Zhou, Jian, Fan, Jia, Ke, Aiwu, Zhou, Lu, Cai, Jiabin
• Format: Journal Article
• Language: English
• Published: Weinheim John Wiley & Sons, Inc 01.10.2023; John Wiley and Sons Inc; Wiley
• Subjects: Algorithms; Biomarkers; Blood clots; carcinogen metabolism; Correlation analysis; Datasets; Ferroptosis; Genes; hepatocellular carcinoma; Immunology; Immunotherapy; Kinases; Liver cancer; Medical prognosis; Metabolism; Regression analysis; Survival analysis
• ISSN: 2198-3844; 2198-3844
• DOI: 10.1002/advs.202301928

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