Integrative Single‐Cell and Spatial Transcriptomics Reveals the Crosstalk of CTHRC1+ CAF and MMP7+ Epithelial Axis as a Potential Therapeutic Target and Predicts Poor Clinical Outcomes in Colorectal Cancer

Background Colorectal cancer (CRC) progression is heavily influenced by the tumor microenvironment (TME), where cancer‐associated fibroblasts (CAFs) are key players. However, the heterogeneity, plasticity, and functional roles of CAFs in CRC remain poorly understood. Methods We integrated single‐cell RNA sequencing (scRNA‐seq) data from four public CRC datasets and spatial transcriptomics data. Using computational approaches such as Harmony, Monocle2, and CellChat algorithms, we analyzed cellular landscapes, CAF subtype identification, developmental trajectories, transcription factor networks, and cell–cell communications to reveal CAF heterogeneity and their crosstalk with other cell subtypes in CRC. Results We identified eight distinct CAF subtypes with unique gene expression profiles and developmental plasticity. The CTHRC1+ CAF subtype was significantly associated with T cell exclusion and upregulated expression of immune checkpoint genes. We uncovered a specific communication axis between CTHRC1+ CAFs and MMP7+ malignant epithelial (Malig‐Epi) cells mediated by the thrombospondin (THBS)2‐SDC4 ligand–receptor signaling. High infiltration of both cell types synergistically correlates with worse prognosis and unfavorable response to immunotherapy. Conclusions Our study delineates CAF heterogeneity in CRC and highlights the CTHRC1+ CAF subtype as a critical organizer of an immunosuppressive niche. The THBS2‐SDC4 signaling pathway between CTHRC1+ CAFs and MMP7+ epithelial cells acts as a potential therapeutic target to disrupt protumorigenic crosstalk and improve clinical outcomes for CRC patients.