A multi-omics dissection of INHBA+ CAF-mediated epithelial-mesenchymal transition and immune suppression in colorectal cancer

BACKGROUND: The progression of colorectal cancer (CRC) is profoundly influenced by the tumor microenvironment (TME). However, the spatial functional specialization of cancer-associated fibroblasts (CAFs) in driving malignancy and immune evasion remains poorly defined. This study aims to delineate the spatial and functional heterogeneity of specific CAF subpopulations in CRC. METHODS: We performed single-cell RNA sequencing (scRNA-seq) on CRC tissues and integrated public datasets to map the stromal landscape. Key cellular interactions inferred from scRNA-seq were validated using high-resolution Xenium in situ transcriptomics and further corroborated by public spatial transcriptomics (ST) data and immunohistochemistry (IHC). RESULTS: CAF lineages coexist: one orchestrating EMT-driven invasion and the other fostering local immunosuppression via Treg recruitment. CONCLUSION: Our study reveals a spatial division of labor among CAFs in CRC. The conserved expression of INHBA across both pro-tumorigenic lineages positions it as a central stromal regulator and a promising therapeutic target for simultaneously disrupting tumor invasion and immune evasion. These findings highlight the potential of stroma-targeted strategies in advancing CRC treatment.