The CXCL12-CXCR4/CXCR7 axis as a therapeutic target in liver cancer: Enhancing immune evasion and the future of combination therapies.

Liver cancer remains one of the leading causes of cancer-related death worldwide, and its immunologically "cold" tumor microenvironment continues to undermine the efficacy of immunotherapy. Among the many stroma-derived factors, C-X-C motif chemokine ligand 12 (CXCL12) is regarded as a central regulator of immune exclusion, mediating limited effector T cell infiltration and promoting tumor progression through C-X-C chemokine receptor type (CXCR) 4 and CXCR7. This review summarizes the latest understanding of the CXCL12-CXCR4/CXCR7 axis in liver cancer, with particular emphasis on the new perspective that cancer-associated fibroblast (CAF) heterogeneity shapes distinct CXCL12 niches, and that CXCL12 constructs a spatial barrier at the tumor margin to reinforce immune privilege. We further evaluate therapeutic strategies targeting this axis, including antagonists, neutralizing antibodies, and novel delivery systems, and explore their combination with immune checkpoint inhibitors (ICIs), emerging immunotherapies, and anti-angiogenic treatments. In addition, we propose the clinical potential of CXCL12-CXCR4/CXCR7 axis-related molecules as predictive biomarkers, highlighting the translational value of resistance mechanisms and immune re-sensitization. Through these new perspectives, this review provides an innovative summary and future research directions for understanding the key role of CXCL12 in the liver cancer immune microenvironment and for developing targeted combination immunotherapy strategies.