CX3CL1/CX3CR1 signaling in spinal metastasis: mechanisms and translational opportunities.

BACKGROUND: Spinal metastases are a common and morbid complication of advanced malignancies. While vertebral involvement is often attributed to anatomical factors, emerging evidence implicates the chemokine CX3CL1 and its receptor in guiding tumor cells to the spine and reshaping the bone microenvironment. OBJECTIVE: To systematically review the role of the CX3CL1/CX3CR1 axis in spinal metastasis from primary breast, prostate, and liver tumours, synthesizing mechanistic, preclinical, and translational findings. METHODS: Following PRISMA guidelines, we searched Medline, EMBASE, Web of Science, and Scopus from inception to May 27, 2025, identifying original studies on CX3CL1/CX3CR1 signalling in spinal metastasis. Ten studies met inclusion criteria. Data were extracted across study design, tumour model, expression analysis, mechanisms, and therapeutic or prognostic outcomes. We also analysed experimentally determined CX3CL1 and CX3CR1 structures to identify features relevant to inhibitor design. RESULTS: CX3CL1 expression was three-fold higher in spinal metastases than in primary tumours or non-spinal bone. Mechanistic studies showed roles in chemotaxis, Src/FAK and PI3K/AKT activation, EMT, vascular permeability, and immunomodulation. CX3CL1 also activated stromal pathways promoting osteolysis. Pharmacologic inhibition reduced spinal metastasis and restored chemosensitivity in murine models. Elevated serum CX3CL1/CX3CR1 levels correlated with disease burden in patient cohorts. CONCLUSION: The CX3CL1/CX3CR1 axis contributes to spinal metastasis by integrating tumour-intrinsic signalling with vertebral niche remodelling, extending the seed-and‑soil hypothesis. Its consistent activity and tractability highlight its promise as both biomarker and therapeutic target in metastatic spine disease.