M. Li, B. Xu, J. Wu, Z. Zhang, B. Chen, Y. Chen, D. Li, X. Tu, K. Wang, Z. Yang, Y. Li, Y. Tan, J. Huang, Y. Ni, Z. Chen, Y. Chen, J. Qiu, S. Zeng, L. Liang
The spatial architecture of the tumor microenvironment (TME) is pivotal in the progression of colorectal cancer (CRC) liver metastasis. By applying high-plex spatial multi-omic mapping and neighborhood analysis to a discovery cohort of colorectal cancer primary tumor (PT) and paired liver metastases (LM), we identified a specialized vimentin-high macrophages-endothelial cells niche that orchestrates cancer-associated fibroblast (CAF) phenotypes. Mechanistically, in primary tumors, vimentin-high macrophages secrete INHBA to activate the ACVR2/TGF-{beta} axis in endothelial cells, driving CAFs toward a myCAF phenotype. Conversely, in liver metastases, these macrophages secrete CXCL9 to trigger the PI3K-Akt/NF-[kcy]B/CXCL12 cascade in endothelial cells, directing CAFs toward an iCAF state. Clinically, high niche activity predicts poor survival. Divergent endothelial signaling in primary versus metastatic lesions exposes site-specific stromal vulnerabilities for therapeutic targeting, with architectural features discernible from routine histopathology. These findings reveal a site-specific regulatory mechanism of the macrophage-endothelial niche, offering a novel and clinically significant biomarker for CRC prognosis.