Zuazo-Gaztelu I, Pàez-Ribes M, Carrasco P, et al. - Given that intratumor hypoxia represents a positive stimulus for invasion by tumor cells and anti-VEGF/R therapies, particularly, cause hypoxia-induced invasion and metastasis in a spontaneous mouse model of pancreatic neuroendocrine cancer, RIP1-Tag2, researchers here report that impaired tumor growth and extended survival were seen in the RIP1-Tag2 model in correlation with the use of a new vascular-targeting agent targeting semaphorin 4D (Sema4D). Although anti-Sema4D therapy did not induce intratumor hypoxia but it led to an increase in local invasion and distant metastases, which was comparable with the one offered by VEGFR inhibition. Overall, anti-Sema4D antibody showed beneficial antitumor and prosurvival effects but also unraveled a new promalignant influence involving macrophage-derived stromal cell–derived factor 1 that favors tumor invasion and metastasis, both in animal models and patients.