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

Area of Science:

• Immunology
• Metabolic pathways
• Hepatocellular Carcinoma (HCC) research

Background:

• Immunotherapy combined with molecular targeted therapy shows promise for HCC.
• The precise mechanisms underlying this combination therapy's efficacy remain unclear.
• Identifying novel therapeutic targets is crucial for advancing HCC treatment.

Purpose of the Study:

• To identify novel immunometabolic targets in HCC.
• To investigate the role of phosphoglycerate mutase 1 (PGAM1) in HCC progression and immunotherapy response.
• To evaluate PGAM1 inhibition as a therapeutic strategy for HCC.

Main Methods:

• Bioinformatic analysis of multiple HCC datasets to identify potential targets.
• In vitro and in vivo experiments to assess the effects of PGAM1 inhibition.
• Assessment of CD8+ T-cell infiltration, ferroptosis, and related molecular pathways (LCN2, AKT, PD-L1).
• Evaluation of a PGAM1 inhibitor (KH3) in patient-derived xenograft (PDX) and HCC models.

Main Results:

• PGAM1 is highly expressed in HCC, correlating with poor prognosis and reduced immunotherapy response.
• Targeting PGAM1 inhibited HCC cell growth and increased CD8+ T-cell infiltration.
• PGAM1 inhibition induced HCC cell ferroptosis via LCN2 downregulation, energy stress, and AKT inhibition.
• Inhibition of PGAM1 reduced PD-L1 expression.
• The PGAM1 inhibitor KH3 demonstrated antitumor effects and enhanced anti-PD-1 immunotherapy efficacy in HCC models.

Conclusions:

• PGAM1 is a novel immunometabolic target in HCC.
• PGAM1 inhibition exerts antitumor effects by promoting ferroptosis and CD8+ T-cell infiltration.
• Targeting PGAM1 represents a promising synergistic strategy with anti-PD-1 immunotherapy for HCC treatment.