ACKR3 (atypical chemokine receptor 3) is a G protein-coupled receptor that functions as a non-canonical chemokine receptor with distinct roles in immune regulation, development, and disease. Primary function: ACKR3 acts as a scavenger receptor for the chemokine CXCL12, competing with the canonical receptor CXCR4 for ligand binding 1. Mechanism: ACKR3 mediates CXCL12 internalization and removal from the environment, and can form heterodimers with CXCR4 to modulate signaling activity 1. Unlike CXCR4, ACKR3 activation triggers β-arrestin-mediated signaling pathways distinct from G protein signaling 2. Disease relevance: ACKR3 plays critical roles in multiple pathological conditions. In cardiovascular disease, ACKR3 exerts atheroprotective, cardioprotective, and anti-thrombotic effects, with enhanced platelet expression associated with improved outcomes following myocardial infarction 32. The CXCL12/CXCR4/ACKR3 axis is implicated in cancer progression through multiple mechanisms affecting tumor cell proliferation, survival, and metastasis 4. Clinical significance: ACKR3 represents a promising therapeutic target, with monoclonal antibodies and small-molecule modulators under development 56. Understanding ACKR3-mediated signaling may enable novel strategies for treating cancer, cardiovascular disease, and inflammatory conditions 7.