Abstract: Atypical chemokine receptor 3 (ACKR3), also known as CXC chemokine receptor 7 (CXCR7), has attracted increasing attention for its regulatory roles in the tumor microenvironment. As a high-affinity receptor for CXCL12, ACKR3 participates in malignant processes such as tumor cell proliferation, angiogenesis, invasion and metastasis, and cancer cachexia. ACKR3 is aberrantly over-expressed in multiple solid tumors such as breast cancer, lung cancer and colorectal cancer, suggesting its potential as a diagnostic and prognostic biomarker. Targeting strategies against ACKR3, such as small-molecule inhibitors and nanobody antagonists, have shown promising antitumor activity in preclinical studies. In addition, combined use of ACKR3 inhibitors with endocrine therapy or immune checkpoint inhibitors has preliminarily demonstrated the potential for synergistic effects. This review systematically summarizes the molecular structure of ACKR3, its signaling regulatory mechanisms, functional heterogeneity across different cancers, and advances in ACKR3-targeted therapies. The clinical translational prospects of ACKR3 as a biomarker and therapeutic target are also discussed, providing new perspectives and a study basis for precision anticancer strategies based on ACKR3.