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

Martine J Smit1, Géraldine Schlecht-Louf2, Maria Neves2,3,4,5

  • 1Department of Medicinal Chemistry, Amsterdam Institute of Molecular and Life Sciences (AIMMS), Faculty of Science, Vrije Universiteit Amsterdam, 1081 HZ Amsterdam, Netherlands;

Annual Review of Pharmacology and Toxicology
|September 21, 2020
PubMed

Insights

The CXCL12/CXCR4/ACKR3 axis drives cancer through complex signaling and immune cell interactions. Targeting this axis, alongside receptor tyrosine kinases or immune cells, offers promising therapeutic strategies for cancer treatment.

Area of Science:

  • Oncology
  • Molecular Biology
  • Immunology

Background:

  • The chemokine pathway involving CXCL12, CXCR4, and ACKR3 is upregulated in various tumors and the tumor microenvironment (TME).
  • The precise mechanisms by which this axis influences cancer pathogenesis remain incompletely understood.
  • This axis plays a role in tumor progression through intricate signaling networks and immune cell modulation.

Purpose of the Study:

  • To elucidate the multifaceted roles of the CXCL12/CXCR4/ACKR3 axis in cancer development.
  • To explore the axis's interactions with signaling pathways and the TME.
  • To review current and novel therapeutic strategies targeting this axis.

Main Methods:

  • Review of existing literature on the CXCL12/CXCR4/ACKR3 axis in cancer.
  • Analysis of molecular mechanisms, including canonical and non-canonical signaling.
  • Examination of crosstalk with receptor tyrosine kinases (RTKs) and immune cells within the TME.

Main Results:

  • The CXCL12/CXCR4/ACKR3 axis impacts diverse cancer cell signaling pathways.
  • Bidirectional crosstalk exists between this axis, RTKs, and other TME components.
  • The axis influences immune cell infiltration, which can promote tumor progression.

Conclusions:

  • Targeting the CXCL12/CXCR4/ACKR3 axis is a key strategy in cancer therapy.
  • Combined targeting of RTKs and the CXCL12/CXCR4/ACKR3 axis presents a viable multitargeted approach.
  • Modulating this axis in conjunction with immune cell inhibition or activation holds significant therapeutic potential.
Keywords:
ACKR3CXCR4GPCRscancerchemokine receptorstherapeutics

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