This study investigates the interactions between hepatocytes and metastatic cells to understand the constraints on metastatic seeding. Using an in vivo CRISPR activation screen, the authors identify plexin B2 as a critical host-derived regulator of liver colonization in colorectal, pancreatic, and melanoma syngeneic mouse models. Plexin B2 interacts with class IV semaphorins on tumor cells, leading to KLF4 upregulation and promoting epithelial traits. The findings highlight the importance of signals from the liver parenchyma for the seeding of disseminated tumor cells before the establishment of a growth-promoting niche. Blocking the plexin-B2–semaphorin axis abolishes metastatic colonization of the liver, suggesting a therapeutic strategy for preventing hepatic metastases. The screening approach, which evaluates host-derived extrinsic signals, is broadly applicable and provides a framework for studying environmental constraints to metastasis in other organs and cancer types.This study investigates the interactions between hepatocytes and metastatic cells to understand the constraints on metastatic seeding. Using an in vivo CRISPR activation screen, the authors identify plexin B2 as a critical host-derived regulator of liver colonization in colorectal, pancreatic, and melanoma syngeneic mouse models. Plexin B2 interacts with class IV semaphorins on tumor cells, leading to KLF4 upregulation and promoting epithelial traits. The findings highlight the importance of signals from the liver parenchyma for the seeding of disseminated tumor cells before the establishment of a growth-promoting niche. Blocking the plexin-B2–semaphorin axis abolishes metastatic colonization of the liver, suggesting a therapeutic strategy for preventing hepatic metastases. The screening approach, which evaluates host-derived extrinsic signals, is broadly applicable and provides a framework for studying environmental constraints to metastasis in other organs and cancer types.