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<p>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 MARCO<sup>hi</sup> 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 <i>Marco</i> 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月24日

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  • Hao Sun,
  • Mengya Gao,
  • Zexing Liu,
  • Zhen Zhang,
  • Xudong Li,
  • Hong Huang,
  • Tiandong Li,
  • Jianxiang Shi,
  • Jiaqin Yan,
  • Mingxia Sun,
  • Miao Liu,
  • Yu An,
  • Siyue Li,
  • Yupeng Liu,
  • Zhenghua Huang,
  • Yuhan Hu,
  • Yuxuan Liu,
  • Chaoge Li,
  • Mengmeng Liu,
  • Meimei Yan,
  • Junfeng Chu,
  • Yongping Song,
  • Jinxin Miao,
  • Mengjia Li,
  • Zhilei Bian,
  • Wei Li,
  • Gangcheng Wang,
  • Binglei Zhang,
  • Shiyu Zuo,
  • Linping Xu

摘要

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.