Abstract
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.
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All data generated in the study are available in the present article, supplementary information, and supplementary data.
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The code supporting this study is not publicly available but will be made available by the corresponding author upon reasonable request.
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Acknowledgements
We would like to thank all our authors listed in this manuscript. This work was supported by Natural Science Foundation of China (82400233 (B.Z.), 82270149 (W.L.), 82370144 (Y.S.)); Henan Province Medical Science and Technology Research Project (SBGJ202002087(H.S.), LHGL20240207 (B.Z.)); The Natural Science Foundation of Henan Province (242300421080 (W.L.)); Leading talent project of Henan Province (LJRC2023004, (L.X.)); Postdoctoral Innovative Talent Support Program (GZC20232429(B.Z.)); Henan Provincial Key R&D Program (251111312100 (H.S.)). Funding for Scientific Research and Innovation Team of The First Affiliated Hospital of Zhengzhou University.
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H.S., M.G., Z.L., and Z.Z. performed experiments, and analyzed the data. B.Z. and S.Z. drafted manuscript. Z.L., Z.Z., T.L., and J.S. analyzed the ScRNA-seq data and bulk-RNA-seq data. H.H., X.L., J.Y., M.S., M.L., Y.A., S.Y., Y.L., Z.H., Y.H., Y.L., C.L., M.L., and M.Y. performed experiments. J.C., Y.S., J.M., M.L., Z.B., and W.L. read and edited the manuscript. L.X., S.Z., B.Z., and G.W. designed and supervised the study and edited the manuscript. All authors approved the final manuscript.
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Sun, H., Gao, M., Liu, Z. et al. Identification and characterization of MARCO-expressing tumor-associated macrophages in pancreatic ductal adenocarcinoma with pan-cancer relevance. npj Precis. Onc. (2026). https://doi.org/10.1038/s41698-026-01293-5
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DOI: https://doi.org/10.1038/s41698-026-01293-5
