SRPX2 aggravates tumor progression and immune resistance through TGFBR2-mediated epithelial–mesenchymal transition in colorectal cancer

Abstract Colorectal cancer (CRC) metastasis presents a formidable clinical challenge, particularly for microsatellite stability (MSS) subtypes that show limited response to current targeted therapies and immunotherapies. While transforming growth factor beta (TGF-β) signaling is recognized as an inducer of the mesenchymal transition program, including epithelial–mesenchymal transition (EMT) and extracellular matrix (ECM) remodeling in metastatic progression, the upstream molecular mechanisms controlling TGF-β pathway activation in metastasis remain unclear. Here, we identified sushi repeat-containing protein X-linked 2 (SRPX2) as a novel metastasis driver that orchestrates TGF-β signaling through an unexpected molecular mechanism. Our multi-omics analysis of metastatic CRC datasets revealed SRPX2 as the top candidate gene associated with aggressive progression and immunotherapy resistance. Mechanistically, SRPX2 binds to and stabilizes TGFBR2, activating the TGF-β signaling pathway that promotes EMT/ECM reprogramming. We further demonstrated that SRPX2 ablation suppresses liver metastasis and enhances tumor sensitivity to immune checkpoint inhibitors, accompanied by reduced mesenchymal abundance. These findings establish SRPX2 as a crucial molecular switch controlling TGF-β pathway activation in CRC metastasis and reveal its dual role in promoting stromal remodeling and immune evasion. Our work provides a compelling rationale for targeting the SRPX2/TGF-β axis as a novel therapeutic strategy for aggressive CRC subsets.