FABP4 Couples Lipid Metabolism to PD-L1 Stabilization in Immunosuppressive Myeloid Cells

Abstract Metabolic dysregulation in obesity reshapes immune function, but how lipid signals drive immune suppression remains unclear. Herein, we identify a FABP4–PD-L1 axis that links lipid metabolism to immune checkpoint regulation in myeloid cells. Single-cell transcriptomics revealed a distinct FABP4high immunosuppressive splenic macrophage subset enriched under high-fat diet (HFD) conditions, characterized by impaired antigen presentation and elevated PD-L1 expression. Mechanistically, palmitic acid (PA) was shown to induce FABP4 and promote PD-L1 palmitoylation, leading to its stabilization on the cell surface independent of transcriptional regulation. FABP4 was essential for this process, which enabled PD-L1 surface stabilization, immunosuppression and mammary tumor progression. In humans, a conserved CD14intCD16⁺ monocyte population exhibited elevated FABP4–PD-L1 signaling and correlated 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 FABP4 as a potential therapeutic target in cancer immunotherapy.