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

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) 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.

Keywords: carcinogen metabolism; ferroptosis; hepatocellular carcinoma; immunotherapy.