The microenvironment of distant organs plays a critical role in modulating tumor metastasis; however, the molecular interactions between metastatic cancer cells and their target organs remain poorly understood. In this study, we identified a marked upregulation of EFNB2 expression in colorectal cancer (CRC) liver metastases (LM), whereas no such increase was observed in pulmonary metastases (PM) or primary CRC tumors. Functional analyses demonstrated that EFNB2 exerts a pro-tumorigenic effect in CRC liver metastasis both in vitro and in vivo. Mechanistically, EFNB2 promotes metastatic growth through forward signaling by engaging the EPHB4 receptor. Activation of the EFNB2–EPHB4 signaling axis enhances low-density lipoprotein receptor (LDLR)–mediated cholesterol uptake in CRC liver metastases. Furthermore, this axis upregulates LDLR transcription by modulating STAT3 phosphorylation. Genetic or pharmacological inhibition of LDLR abrogated the tumor-promoting effects of the EFNB2–EPHB4 pathway in CRC liver metastasis. Analysis of clinical datasets revealed that CRC patients with liver metastases exhibiting high EFNB2 expression had significantly reduced survival compared with those displaying low EFNB2 levels. Consistently, blockade of the EFNB2–EPHB4 axis significantly extended survival in BALB/c nude mice bearing CRC liver metastases under a high-cholesterol diet. Collectively, these findings uncover a critical mechanism by which the EFNB2–EPHB4 axis regulates cholesterol uptake and drives the progression of colorectal cancer liver metastases.
