The CXCL12/CXCR4/ACKR3 Axis in the Tumor Microenvironment: Signaling, Crosstalk, and Therapeutic Targeting

Annu Rev Pharmacol Toxicol. 2021 Jan 6:61:541-563. doi: 10.1146/annurev-pharmtox-010919-023340. Epub 2020 Sep 21.

Abstract

Elevated expression of the chemokine receptors CXCR4 and ACKR3 and of their cognate ligand CXCL12 is detected in a wide range of tumors and the tumor microenvironment (TME). Yet, the molecular mechanisms by which the CXCL12/CXCR4/ACKR3 axis contributes to the pathogenesis are complex and not fully understood. To dissect the role of this axis in cancer, we discuss its ability to impinge on canonical and less conventional signaling networks in different cancer cell types; its bidirectional crosstalk, notably with receptor tyrosine kinase (RTK) and other factors present in the TME; and the infiltration of immune cells that supporttumor progression. We discuss current and emerging avenues that target the CXCL12/CXCR4/ACKR3 axis. Coordinately targeting both RTKs and CXCR4/ACKR3 and/or CXCL12 is an attractive approach to consider in multitargeted cancer therapies. In addition, inhibiting infiltrating immune cells or reactivating the immune system along with modulating the CXCL12/CXCR4/ACKR3 axis in the TME has therapeutic promise.

Keywords: ACKR3; CXCR4; GPCRs; cancer; chemokine receptors; therapeutics.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Chemokine CXCL12
  • Humans
  • Ligands
  • Neoplasms*
  • Receptors, CXCR4
  • Signal Transduction
  • Tumor Microenvironment

Substances

  • CXCL12 protein, human
  • CXCR4 protein, human
  • Chemokine CXCL12
  • Ligands
  • Receptors, CXCR4