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<p>Tumor-associated macrophages (TAMs) are pivotal immunosuppressive components of the tumor microenvironment (TME) in gastric cancer (GC), yet their heterogeneity and metabolic crosstalk with tumor cells remain poorly understood. Here, we performed single-cell RNA sequencing (scRNA-seq) on 75,743 cells from 11 GC tissues and identified four distinct TAM subsets (TAM-APOE, TAM-IDO1, TAM-SKAP1, TAM-POLB), each exhibiting unique functional signatures. Among these, the TAM-APOE subset, enriched in lipid metabolism and complement pathways, showed the strongest interaction with tumor cells via the MIF-CD74 axis. Functional studies revealed that GC-derived MIF promotes TAM-APOE polarization, upregulating immunosuppressive genes and enhancing tumor progression. In vivo, MIF overexpression in GC cells increases subcutaneous tumor volume, while MIF knockdown decreases tumor weight. Crucially, Milatuzumab, a CD74-targeting antibody, reversed MIF-induced TAM immunosuppression in vitro. Our research provides a comprehensive map of GC-TAM heterogeneity; reveals that the MIF-CD74 axis is a key driver of TAM-mediated immune suppression; and proposes that CD74 blockade is a new therapeutic strategy for GC.</p>

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Single-cell RNA sequencing analysis revealed the immunosuppressive remodeling of tumor-associated macrophages mediated by the MIF-CD74 axis in gastric cancer

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年7月24日

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  • Weiwei Liu,
  • Chuangyuan Wang,
  • Lixin Liang,
  • Congcong Zhang,
  • Yanyan Li,
  • Jun Xiao,
  • Rui Zeng,
  • Jingyu Li,
  • Zhihao Lin,
  • Qinghua Huang,
  • Lisheng Zheng,
  • Qingling Zhang

摘要

Tumor-associated macrophages (TAMs) are pivotal immunosuppressive components of the tumor microenvironment (TME) in gastric cancer (GC), yet their heterogeneity and metabolic crosstalk with tumor cells remain poorly understood. Here, we performed single-cell RNA sequencing (scRNA-seq) on 75,743 cells from 11 GC tissues and identified four distinct TAM subsets (TAM-APOE, TAM-IDO1, TAM-SKAP1, TAM-POLB), each exhibiting unique functional signatures. Among these, the TAM-APOE subset, enriched in lipid metabolism and complement pathways, showed the strongest interaction with tumor cells via the MIF-CD74 axis. Functional studies revealed that GC-derived MIF promotes TAM-APOE polarization, upregulating immunosuppressive genes and enhancing tumor progression. In vivo, MIF overexpression in GC cells increases subcutaneous tumor volume, while MIF knockdown decreases tumor weight. Crucially, Milatuzumab, a CD74-targeting antibody, reversed MIF-induced TAM immunosuppression in vitro. Our research provides a comprehensive map of GC-TAM heterogeneity; reveals that the MIF-CD74 axis is a key driver of TAM-mediated immune suppression; and proposes that CD74 blockade is a new therapeutic strategy for GC.