Identification and characterization of MARCO-expressing tumor-associated macrophages in pancreatic ductal adenocarcinoma with pan-cancer relevance

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers worldwide. The role of macrophage receptor with collagenous structure (MARCO), a scavenger receptor class-A protein expressed on macrophage surface, in PDAC progression remains unclear. Here, we identified a subset of MARCO-expressing macrophages with strong immunosuppressive signatures that were markedly increased in PDAC patients. Analysis of MARCOhi PDAC samples displayed reduced proportion of CD8⁺ T cells and NK cells, accompanied by an increased proportion of regulatory T cells (Tregs). In vitro, co-culture with multiple PDAC cell lines potently induced MARCO expression on both human and murine macrophages, driving them to a pro-tumorigenic polarization phenotype. Cell-cell interaction analyses further indicated that vascular endothelial growth factor (VEGF) selectively targets MARCO⁺ macrophages, and VEGF stimulation significantly upregulates MARCO expression in vitro. Notably, genetic ablation of Marco markedly suppressed tumor growth in a murine PDAC model, at least partly through enhanced proportion of NK and T cells. Furthermore, MARCO⁺ macrophages were also enriched across several other cancer types, suggesting a potential pan-cancer relevance. Collectively, our findings uncover a critical role of MARCO⁺ macrophages in PDAC progression and highlight MARCO as a promising therapeutic target with potential applicability across multiple malignancies.