In Silico Single-Cell Transcriptomic Analysis Reveals Senescence-Associated Programs’ Progress Along the Normal–Adenoma–Carcinoma Sequence in Colorectal Cancer

Colorectal cancer (CRC) develops through a multistep progression from normal colonic mucosa to adenoma and ultimately carcinoma. However, the cell-type-specific senescence-associated states during this transition remain incompletely understood. We performed an integrative analysis of single-cell RNA-sequencing and spatial transcriptomic datasets derived from normal mucosa, adenomatous polyps, and primary CRC tissues. Our analyses revealed a progressive increase in senescence-associated transcriptional scores from normal mucosa through adenoma to carcinoma, with the highest senescence scores observed in malignant tissues. This increase was particularly evident in epithelial cells and monocytes. Cell–cell communication analysis identified enhanced macrophage migration inhibitory factor (MIF) signaling between high-senescence-score cells and B-cell populations, primarily through the MIF–CD74/CXCR4 receptor complex. Spatial transcriptomic analysis further showed that high-senescence-score regions were preferentially localized at or near the tumor invasive margin and in proximity to stromal regions, indicating that senescence-associated programs may contribute to the spatial organization of the CRC microenvironment. Together, these findings support a senescence-centered model of colorectal tumor evolution in which epithelial, myeloid, and lymphoid senescence-associated states progressively accumulate and interact through paracrine signaling networks. The MIF–CD74/CXCR4 axis may represent a candidate mediator of senescence-associated tumor–immune interactions and a potential therapeutic target.