Abstract
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.