<p>Tumor-derived elements contribute to the formation of the pre-metastatic niche (PMN) and facilitate cancer metastasis, but much less is known about the key molecular mechanisms. Here, we demonstrate that collapsin response mediator protein 2 (CRMP2), a critical regulator of the cytoskeleton, is associated with metastasis in breast cancer. CRMP2 overexpression inhibits both lung metastasis and PMN formation in breast cancer. Mechanistically, CRMP2 overexpression leads to downregulation of CXCL10. We also found that the correlation between CRMP2 and CXCL10 is mediated by interleukin enhancer-binding factor 3 (ILF3). The D-hydantoinases (D-HYD) fragment of CRMP2 specifically interacts with the second double-stranded RNA binding motif (dsRBM2) of ILF3. Overexpressed CRMP2 reduces the expression of ILF3 in proteasome-dependent degradation via Lys 48-linked polyubiquitination at Lys²⁵⁷, Lys³³² and Lys⁴¹³. In addition, ILF3 directly binds to CXCL10 mRNA, thereby increasing CXCL10 mRNA stability. Finally, we found that psoralen interacts with CRMP2 and suppresses the development of lung metastases in breast cancer. In conclusion, our findings uncover a critical CRMP2-related mechanism behind breast tumor metastasis, and the CRMP2-ILF3-CXCL10 axis may provide a potential therapeutic strategy for controlling breast cancer metastasis.</p><p></p>