The CXCL12-CXCR4 axis in colorectal cancer: immune regulation, metastatic progression, and therapeutic implications

Metastasis remains the major cause of mortality in colorectal cancer (CRC) despite continued advances in diagnosis and treatment. Increasing evidence identifies the CXCL12/CXCR4 chemokine axis as a critical driver of CRC progression and metastatic dissemination. Through dynamic interactions between tumor cells and the tumor microenvironment, this axis regulates multiple processes essential for metastasis, including driving migration and invasion, angiogenesis and lymphangiogenesis, and shaping the tumor immune microenvironment through recruitment of immunosuppressive populations, blockade of effector lymphocyte trafficking and function, and modulation of immunosuppressive cytokines including IL-10. In this review, we summarize the molecular mechanisms by which CXCL12/CXCR4 promotes CRC metastasis. These pleiotropic effects are mediated by crosstalk with PI3K/Akt, MAPK/ERK, and Wnt/β-catenin pathways, and are regulated at transcriptional, post-transcriptional, and post-translational levels. Preclinical studies demonstrate that CXCR4 antagonists (e.g., plerixafor, LY2510924) suppress metastasis and, when combined with immune checkpoint inhibitors, can reverse the "cold" immune phenotype of microsatellite-stable CRC. We also discuss recent advances in the regulation of CXCL12/CXCR4 expression, the role of related receptors such as CXCR7, and emerging strategies targeting this axis for therapeutic intervention. Collectively, current evidence supports the CXCL12/CXCR4 axis as a promising biomarker and therapeutic target in metastatic CRC, and further elucidation of its regulatory network may facilitate the development of more effective precision treatment strategies.