Atypical chemokine receptors: emerging therapeutic targets in cancer

Atypical chemokine receptors (ACKRs) regulate the availability of chemokines via chemokine scavenging, while also having the capacity to elicit downstream function through β-arrestin coupling. This contrasts with conventional chemokine receptors that directly elicit immune cell migration through G protein-coupled signaling. The significance of ACKRs in cancer biology has previously been poorly understood, but recent findings have highlighted the multifaceted role of these receptors in tumorigenesis and immune response modulation within the tumor microenvironment (TME). Additionally, recent research has expanded our understanding of the function of several receptors including GPR182, CCRL2, GPR1, PITPNM3, and C5aR2 that share similarities with the ACKR family. In this review, we discuss these recent developments, and highlight the opportunities and challenges of pharmacologically targeting ACKRs in cancer. Atypical chemokine receptors (ACKRs) are expressed on diverse cell types including blood and lymphatic endothelium cells, coordinate immune cell trafficking through chemokine scavenging, and are biased towards β-arrestin coupling.The ACKR family has been formally recognized as consisting of ACKR1–4. Recent research has identified additional receptors that share some or all of the atypical biological characteristics of ACKRs, including GPR182, CCRL2, GPR1, PITPNM3, and C5aR2.ACKRs play two roles in cancer progression. First, cancer-associated stromal cell expression of ACKRs alters the immune response within the tumor microenvironment (TME) through chemokine scavenging and regulation of immune cell homing. Second, ACKR expression by cancer cells directly impacts tumorigenesis.ACKRs can be directly targeted in cancer therapy due to their intrinsic effects on tumorigenesis. However, the most promising area of ACKR targeted therapies in cancer treatment is targeting ACKRs to modulate the immune response in the TME in conjunction with immunotherapy.