Metabolic regulation and immunosuppressive functions of lipid-associated macrophages in pancreatic ductal adenocarcinoma

Introduction: Pancreatic ductal adenocarcinoma (PDAC) exhibits a profoundly immunosuppressive tumor microenvironment, with tumor-associated macrophages (TAMs) being the most abundant immune infiltrate. Among them, lipid-associated macrophages (LAMs) have emerged as a distinct subpopulation driving immune evasion through metabolic reprogramming. Methods: We conducted a narrative review by systematically searching PubMed, Web of Science, and Scopus for articles on LAMs in PDAC up to December 2023. Key themes were synthesized to cover defining markers, metabolic pathways, immunosuppressive functions, and therapeutic strategies. Results: LAMs are characterized by co-expression of TREM2, APOE, CD9, and lipid-handling genes, and their accumulation correlates with poor prognosis. They undergo metabolic rewiring involving CD36-mediated lipid uptake, dysregulated cholesterol efflux, fatty acid oxidation, and de novo lipogenesis, which collectively enforce an immunosuppressive phenotype. LAMs interact bidirectionally with cancer-associated fibroblasts and directly suppress CD8+ T cells and NK cells. Preclinical targeting of CD36, TREM2, or FAO shows promise but faces challenges in toxicity and delivery. Discussion: LAMs represent a potential therapeutic vulnerability in PDAC, but the field is still in its early stages. Future work should focus on establishing causal evidence in PDAC-specific models, developing tumor-selective delivery systems, and validating biomarkers for patient stratification.