Fibrates Inhibit PLTP‐induced M2 Macrophage Infiltration and Increase the Sensitivity of Hepatocellular Carcinoma to ICIs

High levels of M2 macrophages in the hepatocellular carcinoma (HCC) tumor microenvironment (TME) are associated with poor response to immune checkpoint inhibitors (ICIs). This study comprehensively investigated the role of phospholipid transfer protein (PLTP) in driving M2 macrophage polarization through bioinformatics, clinicopathological analysis, molecular docking, proteomics, biochemical and cellular assays. Additionally, strategies to enhance ICIs sensitivity are validated in multiple animal models. Results demonstrated that high M2 macrophage infiltration independently predicted inferior ICIs outcomes, and PLTP overexpression in HCC promoted M2 macrophage polarization. Mechanistically, PLTP bound to aurora kinase A (AURKA) and P65, forming a complex that induced P65 phosphorylation, thereby activating NF-κB and upregulating IL-6, IL-8, and CSF-1. Molecular docking revealed that GMB-475 specifically bound to PLTP's functional domain (25-245 AA), which competitively inhibited PLTP-P65-AURKA interactions and suppressing P65 phosphorylation. In vivo, GMB-475 reduced M2 macrophage infiltration and suppressed tumor growth. Fibrates downregulated PLTP expression, decreased P65 phosphorylation, and synergized with ICIs in orthotopic and Myc-driven HCC models. These findings highlight PLTP as a key mediator of M2 macrophage polarization via AURKA-dependent NF-κB activation. Targeting PLTP with inhibitor GMB-475 or fibrates may improve ICIs efficacy, offering a promising therapeutic strategy for HCC.