The Role of CAF‐derived Vitronectin in Promoting Colorectal Cancer Progression and Immunosuppression

Cancer-associated fibroblasts (CAFs) dominate the tumor stroma in colorectal cancer (CRC), fostering an immunosuppressive microenvironment that supports tumor growth, metastasis, and therapy resistance. Targeting CAF-derived cytokines and secreted proteins offers potential new avenues for CRC treatment. Here, vitronectin (VTN) is identified as a significantly up-regulated gene in CAFs, correlated with poor prognosis in CRC patients, through multi-dataset analysis and multiplex immunofluorescence. Comprehensive analyses, including cytometry by time -of- flight (CyTOF), in vitro co-culture assays, transgenic mouse models, and azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced CRC models, demonstrate that VTN enhances CRC proliferation, metastasis, and resistance to therapy. CyTOF analysis shows a reduced proportion of M2-type macrophages in fibroblast-specific VTN knockout mice (Vtn^fl/fl S100a4-Cre⁺), with VTN promoting M2 macrophage polarization in vitro. Mechanistically, VTN upregulates SLC6A8 expression in CRC cells and macrophages by enhancing FAK phosphorylation, which increases creatine and ATP uptake, promoting cancer progression and macrophage polarization. Targeted VTN knockout in fibroblasts significantly improves the efficacy of immunotherapies and reduces CRC progression. These findings highlight the dual role of CAF-derived VTN in driving CRC malignancy and modulating immune responses, positioning VTN as a promising therapeutic target in CRC management.