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

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 support tumor 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.

Automated summary

The elevated expression of chemokine receptors CXCR4 and ACKR3 and their ligand CXCL12 in tumors and the tumor microenvironment has led to complex research on their contribution to cancer pathogenesis. Discussions include their impact on signaling networks, crosstalk with RTKs and other TME factors, as well as the infiltration of immune cells supporting tumor progression. Targeting the CXCL12/CXCR4/ACKR3 axis along with RTKs and immune cells modulation shows promising therapeutic potential in multitargeted cancer therapies.