A study reveals that liver-derived plexin B2 is critical for liver colonization by metastatic cancer cells. Using an in vivo CRISPR activation screen, researchers identified plexin B2 as a key host factor that interacts with class IV semaphorins on tumor cells, leading to KLF4 upregulation and promoting epithelial traits in metastatic cells. This interaction is essential for the adaptation of colorectal cancer (CRC) metastases to the liver environment. Blocking the plexin-B2–semaphorin axis prevents liver metastasis, suggesting it as a potential therapeutic strategy. The study also highlights the importance of liver parenchyma signals in enabling metastatic seeding before the establishment of a growth-promoting niche. The screening approach, which evaluates host-derived extrinsic signals, provides a framework for identifying environmental constraints to metastasis in other organs and cancer types. The findings demonstrate that plexin B2 is required for liver seeding and that its interaction with semaphorins is necessary for metastatic colonization. The study further shows that plexin B2 induces epithelialization of liver metastases by reactivating KLF4, which suppresses epithelial-mesenchymal transition (EMT). These results underscore the role of host-derived factors in metastatic seeding and provide insights into the mechanisms underlying liver metastasis.A study reveals that liver-derived plexin B2 is critical for liver colonization by metastatic cancer cells. Using an in vivo CRISPR activation screen, researchers identified plexin B2 as a key host factor that interacts with class IV semaphorins on tumor cells, leading to KLF4 upregulation and promoting epithelial traits in metastatic cells. This interaction is essential for the adaptation of colorectal cancer (CRC) metastases to the liver environment. Blocking the plexin-B2–semaphorin axis prevents liver metastasis, suggesting it as a potential therapeutic strategy. The study also highlights the importance of liver parenchyma signals in enabling metastatic seeding before the establishment of a growth-promoting niche. The screening approach, which evaluates host-derived extrinsic signals, provides a framework for identifying environmental constraints to metastasis in other organs and cancer types. The findings demonstrate that plexin B2 is required for liver seeding and that its interaction with semaphorins is necessary for metastatic colonization. The study further shows that plexin B2 induces epithelialization of liver metastases by reactivating KLF4, which suppresses epithelial-mesenchymal transition (EMT). These results underscore the role of host-derived factors in metastatic seeding and provide insights into the mechanisms underlying liver metastasis.