Impeding macrophage entry into hypoxic tumor areas by Sema3A/Nrp1 signaling blockade inhibits angiogenesis and restores antitumor immunity

Cancer Cell. 2013 Dec 9;24(6):695-709. doi: 10.1016/j.ccr.2013.11.007.


Recruitment of tumor-associated macrophages (TAMs) into avascular areas sustains tumor progression; however, the underlying guidance mechanisms are unknown. Here, we report that hypoxia-induced Semaphorin 3A (Sema3A) acts as an attractant for TAMs by triggering vascular endothelial growth factor receptor 1 phosphorylation through the associated holoreceptor, composed of Neuropilin-1 (Nrp1) and PlexinA1/PlexinA4. Importantly, whereas Nrp1 levels are downregulated in the hypoxic environment, Sema3A continues to regulate TAMs in an Nrp1-independent manner by eliciting PlexinA1/PlexinA4-mediated stop signals, which retain them inside the hypoxic niche. Consistently, gene deletion of Nrp1 in macrophages favors TAMs' entrapment in normoxic tumor regions, which abates their pro-angiogenic and immunosuppressive functions, hence inhibiting tumor growth and metastasis. This study shows that TAMs' heterogeneity depends on their localization, which is tightly controlled by Sema3A/Nrp1 signaling.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Hypoxia
  • Macrophages / drug effects
  • Macrophages / physiology*
  • Mice
  • Mice, Knockout
  • Neoplasms, Experimental / blood supply*
  • Neoplasms, Experimental / immunology
  • Neoplasms, Experimental / pathology
  • Neovascularization, Pathologic / prevention & control*
  • Neuropilin-1 / antagonists & inhibitors
  • Neuropilin-1 / genetics
  • Neuropilin-1 / physiology*
  • Semaphorin-3A / antagonists & inhibitors
  • Semaphorin-3A / physiology*
  • Signal Transduction / physiology*


  • Sema3a protein, mouse
  • Semaphorin-3A
  • Neuropilin-1