• Viruses hijack the CXCL12–CXCR4/CXCR7 chemokine axis • Viral proteins rewire CXCR4/CXCR7 signaling and receptor dynamics • Viruses alter CXCL12 gradients and chemokine spatial distribution • Axis modulation redirects immune cell trafficking during infection • Viral targeting of this axis drives persistence and oncogenesis The CXCL12/CXCR4/CXCR7 chemokine axis is a spatial signaling network that links cell positioning to immune function, tissue repair, vascular stability, and niche retention. Under physiological conditions, CXCL12 gradients, receptor bias, receptor crosstalk, and ligand scavenging coordinate leukocyte trafficking, stem/progenitor-cell localization, endothelial integrity, and tissue remodeling. Viruses frequently exploit this system to facilitate entry, dissemination, immune evasion, persistence, and, in some contexts, virus-associated oncogenesis. Across herpesviruses, retro/lentiviruses, hepatotropic viruses, respiratory viruses, HPV, and neurotropic viruses, several recurring strategies emerge: receptor-interface remodeling through heterodimerization, allosteric modulation, or viral GPCR activity; post-translational modification of receptors, including tyrosine sulfation; transcriptional, epigenetic, and miRNA-mediated regulation that sustains CXCL12 production or shifts CXCR4/CXCR7 expression; and redistribution or sequestration of CXCL12 within tissue microenvironments. These mechanisms reshape antiviral immunity by altering leukocyte recruitment, promoting localized inflammation, restricting effector-cell access, and supporting immune-suppressive niches. In virus-associated cancers, CXCL12-axis rewiring contributes to EMT, invasion, angiogenesis, stromal co-option, immune exclusion, and therapy resistance. In this review, we discuss how diverse viruses reprogram the CXCL12–CXCR4–CXCR7/ACKR3 axis at molecular and spatial levels and connect these changes to immune mislocalization, viral persistence, and oncogenic progression. We also evaluate therapeutic opportunities, including CXCR4/CXCR7 antagonists, CXCL12-neutralizing strategies, and biomarker-guided combinations with targeted therapies or immunotherapies. We propose that this axis should be approached not as a uniformly pathogenic pathway, but as a context-dependent spatial system whose therapeutic modulation must be tailored to viral species, tissue compartment, disease stage, and receptor state.
Sayed et al. (Fri,) studied this question.