Our study showed that CX3CL1/ICAM-1 facilitated spinal metastasis of NSCLC in dual-directional ways, namely improving VBMEC permeability and enhancing tumor cell adhesion and invasion in the context of tumor-stromal interactions, revealing three roles of CX3CL1 in directing circulating NSCLC cell extravasation to trigger spinal metastasis. Here, CX3CL1 is linked to non-small cell lung carcinoma.