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Background <p>Colon cancer remains one of the leading causes of cancer-related mortality globally. Tumor-associated macrophages (TAMs) are key contributors to tumor progression within the tumor microenvironment (TME). However, the role of secreted phosphoprotein 1 (SPP1), a critical regulator of macrophage–tumor interactions, in specific macrophage subsets in colon cancer remains unclear.</p> Methods <p>We performed single-cell RNA sequencing (scRNA-seq) on tumor and adjacent normal tissues from three colon cancer patients. A comprehensive analysis integrating pseudotime trajectory, transcription factor network, cell–cell communication, and in silico SPP1 knockout modeling was conducted to characterize macrophage heterogeneity and function.</p> Results <p>Five macrophage subtypes were identified. Among them, the Macrophages_SPP1 was significantly enriched in tumors and exhibited enhanced glycolytic metabolism, lysosomal activity, angiogenesis, and immunosuppression functions. This subtype showed increased interactions with fibroblasts, particularly via FTL–SCARA5 and FTH1–SCARA5 ligand–receptor pairs, implicating roles in stromal remodeling. In silico SPP1 knockout identified 93 stable responsive genes enriched in MHC class II-related and immune regulatory pathways, highlighting the role of SPP1 in shaping an immunosuppressive TME.</p> Conclusions <p>The Macrophages_SPP1 subtype may contribute to colon cancer progression through metabolic reprogramming and stromal interactions, suggesting that SPP1 and the FTL–SCARA5 axis could represent potential therapeutic targets.</p>

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Single-cell transcriptomic analysis reveals the heterogeneity and functional characteristics of macrophage subpopulations in colon cancer

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月23日

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  • Jiazheng Zhao,
  • Baochun Wang,
  • Xiao Li,
  • Chunting Wei,
  • Yi Min,
  • Dayong Wang

摘要

Background

Colon cancer remains one of the leading causes of cancer-related mortality globally. Tumor-associated macrophages (TAMs) are key contributors to tumor progression within the tumor microenvironment (TME). However, the role of secreted phosphoprotein 1 (SPP1), a critical regulator of macrophage–tumor interactions, in specific macrophage subsets in colon cancer remains unclear.

Methods

We performed single-cell RNA sequencing (scRNA-seq) on tumor and adjacent normal tissues from three colon cancer patients. A comprehensive analysis integrating pseudotime trajectory, transcription factor network, cell–cell communication, and in silico SPP1 knockout modeling was conducted to characterize macrophage heterogeneity and function.

Results

Five macrophage subtypes were identified. Among them, the Macrophages_SPP1 was significantly enriched in tumors and exhibited enhanced glycolytic metabolism, lysosomal activity, angiogenesis, and immunosuppression functions. This subtype showed increased interactions with fibroblasts, particularly via FTL–SCARA5 and FTH1–SCARA5 ligand–receptor pairs, implicating roles in stromal remodeling. In silico SPP1 knockout identified 93 stable responsive genes enriched in MHC class II-related and immune regulatory pathways, highlighting the role of SPP1 in shaping an immunosuppressive TME.

Conclusions

The Macrophages_SPP1 subtype may contribute to colon cancer progression through metabolic reprogramming and stromal interactions, suggesting that SPP1 and the FTL–SCARA5 axis could represent potential therapeutic targets.