FABP4 Couples Lipid Metabolism to PD-L1 Stabilization in Immunosuppressive Macrophages

Abstract

Metabolic dysregulation in obesity reshapes immune function, but how lipid signals drive immune suppression remains unclear. Here, we identify a FABP4-PD-L1 axis that links lipid metabolism to immune checkpoint regulation in monocytes and macrophages. Single-cell transcriptomics revealed a distinct FABP4high immunosuppressive macrophage subset enriched under high-fat diet (HFD) conditions, characterized by impaired antigen presentation and elevated PD-L1 expression. Mechanistically, palmitic acid (PA) induces FABP4 and promotes PD-L1 palmitoylation, leading to its stabilization on the cell surface independent of transcriptional regulation. FABP4 is essential for this process, which enables PD-L1 surface stabilization, immunosuppression and mammary tumor progression. In humans, a conserved CD14intCD16 monocyte population exhibits elevated FABP4-PD-L1 signaling and correlates with obesity and invasive breast cancer. These findings establish PD-L1 as a metabolically regulated protein and reveal a mechanism by which lipid excess drives immune evasion, suggesting that targeting FABP4 may enhance responses to immune checkpoint blockade. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/717546v1_ufig1.gif" ALT="Figure 1"> View larger version (50K): org.highwire.dtl.DTLVardef@1fe3f2corg.highwire.dtl.DTLVardef@e587a7org.highwire.dtl.DTLVardef@12d0f75org.highwire.dtl.DTLVardef@151f916_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIFABP4 defines a lipid-responsive, immunosuppressive monocyte/macrophage subset C_LIO_LIFABP4 links lipid sensing to PD-L1 expression in macrophages C_LIO_LIFABP4 enables palmitic acid-dependent PD-L1 palmitoylation and stabilization C_LIO_LIFABP4-PD-L1 signaling correlates with obesity and invasive breast cancer in humans C_LI