非典型趋化因子受体 ACKR3 在肿瘤中的研究进展

Research progress on the atypical chemokine receptor ACKR3 in cancer

摘要

非典型趋化因子受体 3（ACKR3），亦称 CXC 趋化因子受体 7（CXCR7），在肿瘤微环境中的调控作用日益受到关注。作为 CXCL12 的高亲和力受体，参与肿瘤细胞增殖、血管生成、侵袭转移及癌症恶病质等恶性进程，在乳腺癌、肺癌、结直肠癌等多种实体肿瘤中异常高表达，展现出作为诊断与预后生物标志物的潜力。针对 ACKR3 的靶向策略，包括小分子抑制剂、纳米抗体拮抗剂等，已在临床前研究中显示出良好的抗肿瘤活性。此外，ACKR3 抑制剂与内分泌治疗、免疫检查点抑制剂的联合应用，初步展现出协同增效的前景。文章系统综述了 ACKR3 的分子结构、信号调控机制、在各类肿瘤中的功能异质性及其靶向治疗进展，并探讨了其作为生物标志物与治疗靶点的临床转化前景，为基于 ACKR3 的精准抗癌策略提供了新视角和研究基础。

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.

关键词

非典型趋化因子受体 3 / 趋化因子 / 肿瘤微环境 / 信号通路 / 靶向治疗

Key words

Atypical chemokine receptor 3 / Chemokines / Tumor microenvironment / Signal pathway / Targeted therapy

参考文献

[1] SOERJOMATARAM I, BRAY F . Planning for tomorrow: global cancer incidence and the role of prevention 2020-2070[J]. Nat Rev Clin Oncol, 2021, 18(10): 663-672. DOI: 10.1038/s41571-021-00514-z.

[2] DEL PRETE A, SCHIOPPA T, TIBERIO L, et al. Leukocyte trafficking in tumor microenvironment[J]. Curr Opin Pharmacol, 2017, 35: 40-47. DOI: 10.1016/j.coph.2017.05.004.

[3] BURNS J M, SUMMERS B C, WANG Y, et al. A novel chemokine receptor for SDF-1 and I-TAC involved in cell survival, cell adhesion, and tumor development[J]. J Exp Med, 2006, 203(9): 2201-2213. DOI: 10.1084/jem.20052144.

[4] NGUYEN H T, REYES-ALCARAZ A, YONG H J, et al. CXCR7: a β-arrestin-biased receptor that potentiates cell migration and recruits β-arrestin2 exclusively through Gβγ subunits and GRK2[J]. Cell Biosci, 2020, 10(1): 134. DOI: 10.1186/s13578-020-00497-x.

[5] LIU B, SONG S, SETROIKROMO R, et al. CX chemokine receptor 7 contributes to survival of KRAS-mutant non-small cell lung cancer upon loss of epidermal growth factor receptor[J]. Cancers, 2019, 11(4): 455. DOI: 10.3390/cancers11040455.

[6] WANG T, WANG D, SUN Y, et al. Regulation of the Hippo/YAP axis by CXCR7 in the tumorigenesis of gastric cancer[J]. J Exp Clin Cancer Res, 2023, 42(1): 297. DOI: 10.1186/s13046-023-02870-3.

[7] TANG C, LI L, XU Q, et al. ACKR3 orchestrates Hedgehog signaling to promote renal cell carcinoma progression[J]. Mol Carcinog, 2023, 62(6): 882-893. DOI: 10.1002/mc.23532.

[8] HOY J J, KALLIFATIDIS G, SMITH D K, et al. Inhibition of androgen receptor promotes CXC-chemokine receptor 7-mediated prostate cancer cell survival[J]. Sci Rep, 2017, 7(1): 3058. DOI: 10.1038/s41598-017-02918-3.

[9] HAO M, WENG X, WANG Y, et al. Targeting CXCR7 improves the efficacy of breast cancer patients with tamoxifen therapy[J]. Biochem Pharmacol, 2018, 147: 128-140. DOI: 10.1016/j.bcp.2017.11.013.

[10] MA J, SONG J, YI X, et al. Enhanced T cell immune activity mediated by Drp1 promotes the efficacy of PD-1 inhibitors in treating lung cancer[J]. Cancer Immunol Immunother, 2024, 73(2): 40. DOI: 10.1007/s00262-023-03582-5.

[11] LIBERT F, PARMENTIER M, LEFORT A, et al. Complete nucleotide sequence of a putative G protein coupled receptor: RDC7[J]. Nucleic Acids Res, 1990, 18(7): 1915. DOI: 10.1093/nar/18.7.1915.

[12] NIBBS R J B, GRAHAM G J . Immune regulation by atypical chemokine receptors[J]. Nat Rev Immunol, 2013, 13(11): 815-829. DOI: 10.1038/nri3544.

[13] GRAHAM G J, LOCATI M, MANTOVANI A, et al. The biochemistry and biology of the atypical chemokine receptors[J]. Immunol Lett, 2012, 145(1/2): 30-38. DOI: 10.1016/j.imlet.2012.04.004.

[14] LATAILLADE J J, DOMENECH J, LE BOUSSE-KERDILÈS M C . Stromal cell-derived factor-1 (SDF-1)/CXCR4 couple plays multiple roles on haematopoietic progenitors at the border between the old cytokine and new chemokine worlds: survival, cell cycling and trafficking[J]. Eur Cytokine Netw, 2004, 15(3): 177-188.

[15] HUYNH C, DINGEMANSE J, MEYER ZU SCHWABEDISSEN H E, et al. Relevance of the CXCR4/CXCR7-CXCL12 axis and its effect in pathophysiological conditions[J]. Pharmacol Res, 2020, 161: 105092. DOI: 10.1016/j.phrs.2020.105092.

[16] HOFFMANN F, MÜLLER W, SCHÜTZ D, et al. Rapid uptake and degradation of CXCL12 depend on CXCR7 carboxyl-terminal serine/threonine residues[J]. J Biol Chem, 2012, 287(34): 28362-28377. DOI: 10.1074/jbc.M111.335679.

[17] PUCHERT M, ENGELE J . The peculiarities of the SDF-1/CXCL12 system: in some cells, CXCR4 and CXCR7 sing solos, in others, they sing duets[J]. Cell Tissue Res, 2014, 355(2): 239-253. DOI: 10.1007/s00441-013-1747-y.

[18] ZARCA A, PEREZ C, VAN DEN BOR J, et al. Differential involvement of ACKR3 C-tail in β-arrestin recruitment, trafficking and internalization[J]. Cells, 2021, 10(3): 618. DOI: 10.3390/cells10030618.

[19] SCHAFER C T, CHEN Q, TESMER J J G, et al. Atypical chemokine receptor 3 ‘senses’ CXC chemokine receptor 4 activation through GPCR kinase phosphorylation[J]. Mol Pharmacol, 2023, 104(4): 174-186. DOI: 10.1124/molpharm.123.000710.

[20] LEVOYE A, BALABANIAN K, BALEUX F, et al. CXCR7 heterodimerizes with CXCR4 and regulates CXCL12-mediated G protein signaling[J]. Blood, 2009, 113(24): 6085-6093. DOI: 10.1182/blood-2008-12-196618.

[21] MIEKUS K, JAROCHA D, TRZYNA E, et al. Role of I-TAC-binding receptors CXCR3 and CXCR7 in proliferation, activation of intracellular signaling pathways and migration of various tumor cell lines[J]. Folia Histochem Cytobiol, 2010, 48(1): 104-111. DOI: 10.2478/v10042-008-0091-7.

[22] BEHNAM AZAD B, LISOK A, CHATTERJEE S, et al. Targeted imaging of the atypical chemokine receptor 3 (ACKR3/CXCR7) in human cancer xenografts[J]. J Nucl Med, 2016, 57(6): 981-988. DOI: 10.2967/jnumed.115.167932.

[23] SINGH R K, LOKESHWAR B L . The IL-8-regulated chemokine receptor CXCR7 stimulates EGFR signaling to promote prostate cancer growth[J]. Cancer Res, 2011, 71(9): 3268-3277. DOI: 10.1158/0008-5472.CAN-10-2769.

[24] KIM N, RYU H, KIM S, et al. CXCR7 promotes migration and invasion in head and neck squamous cell carcinoma by upregulating TGF-β1/Smad2/3 signaling[J]. Sci Rep, 2019, 9(1): 18100. DOI: 10.1038/s41598-019-54705-x.

[25] SHI A, WANG T, JIA M, et al. Effects of SDF-1/CXCR7 on the migration, invasion and epithelial-mesenchymal transition of gastric cancer cells[J]. Front Genet, 2021, 12: 760048. DOI: 10.3389/fgene.2021.760048.

[26] CUI Q, LI S, LIU X, et al. MIF-ACKR3 causes irreversible fat loss by impairing adipogenesis in cancer cachexia[J]. Cell Metab, 2025, 37(4): 954-970.e8. DOI: 10.1016/j.cmet.2025.01.018.

[27] YAMADA K, MAISHI N, AKIYAMA K, et al. CXCL12-CXCR7 axis is important for tumor endothelial cell angiogenic property[J]. Int J Cancer, 2015, 137(12): 2825-2836. DOI: 10.1002/ijc.29655.

[28] KOCH C, ENGELE J . Functions of the CXCL12 receptor ACKR3/CXCR7-what has been perceived and what has been overlooked[J]. Mol Pharmacol, 2020, 98(5): 577-585. DOI: 10.1124/molpharm.120.000056.

[29] YUAN C L, LIU Z H, ZOU N, et al. Relationship between expression of CXCR7 and NF-κB in breast cancer tissue and occurrence of breast cancer and lymphatic metastasis[J]. Saudi J Biol Sci, 2017, 24(8): 1767-1770. DOI: 10.1016/j.sjbs.2017.11.009.

[30] NEVES M, MAROLDA V, MAYOR F, et al. Crosstalk between CXCR4/ACKR3 and EGFR signaling in breast cancer cells[J]. Int J Mol Sci, 2022, 23(19): 11887. DOI: 10.3390/ijms231911887.

[31] MIAO Z, LUKER K E, SUMMERS B C, et al. CXCR7 (RDC1) promotes breast and lung tumor growth in vivo and is expressed on tumor-associated vasculature [J]. Proc Natl Acad Sci USA, 2007, 104(40): 15735-15740. DOI: 10.1073/pnas.0610444104.

[32] STACER A C, FENNER J, CAVNAR S P, et al. Endothelial CXCR7 regulates breast cancer metastasis[J]. Oncogene, 2016, 35(13): 1716-1724. DOI: 10.1038/onc.2015.236.

[33] HAO H, TIAN W, GONG J, et al. Targeting the CXCR7 pathway with TC14012 to inhibit endothelial necroptosis and lung cancer metastasis[J]. Biochem Pharmacol, 2025, 236: 116852. DOI: 10.1016/j.bcp.2025.116852.

[34] BRAY F, LAVERSANNE M, SUNG H, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J]. CA Cancer J Clin, 2024, 74(3): 229-263. DOI: 10.3322/caac.21834.

[35] LIU H, CHENG Q, XU D S, et al. Overexpression of CXCR7 accelerates tumor growth and metastasis of lung cancer cells[J]. Respir Res, 2020, 21(1): 287. DOI: 10.1186/s12931-020-01518-6.

[36] WU Y C, TANG S J, SUN G H, et al. CXCR7 mediates TGFβ1-promoted EMT and tumor-initiating features in lung cancer[J]. Oncogene, 2016, 35(16): 2123-2132. DOI: 10.1038/onc.2015.274.

[37] 袁思敏, 李亚玲, 李长天. CXCL12-CXCR4/CXCR7 轴在胃癌中作用的研究进展[J]. 临床与病理杂志, 2023, 43(9): 1683-1689. DOI: 10.11817/j.issn.2095-6959.2023.230082.

[38] YUAN S M, LI Y L, LI C T. Research progress in the role of CXCL12-CXCR4/CXCR7 axis in gastric cancer[J]. J Clin Pathol Res, 2023, 43(9): 1683-1689. DOI: 10.11817/j.issn.2095-6959.2023.230082.

[39] CAO Y, SONG J, GE J, et al. MicroRNA-100 suppresses human gastric cancer cell proliferation by targeting CXCR7[J]. Oncol Lett, 2018, 15(1): 453-458. DOI: 10.3892/ol.2017.7305.

[40] LI D, LI Q . microRNA-200b-3p restrains gastric cancer cell proliferation, migration, and invasion via C-X-C motif chemokine ligand 12/CXC chemokine receptor 7 axis [J]. Bioengineered, 2022, 13(3): 6509-6520. DOI: 10.1080/21655979.2022.2034585.

[41] LI X X, ZHENG H T, HUANG L Y, et al. Silencing of CXCR7 gene represses growth and invasion and induces apoptosis in colorectal cancer through ERK and β-arrestin pathways[J]. Int J Oncol, 2014, 45(4): 1649-1657. DOI: 10.3892/ijo.2014.2547.

[42] LI X, WANG X, LI Z, et al. Chemokine receptor 7 targets the vascular endothelial growth factor via the AKT/ERK pathway to regulate angiogenesis in colon cancer [J]. Cancer Med, 2019, 8(11): 5327-5340. DOI: 10.1002/cam4.2426.

[43] YANG J, MIAO R R, LI Y N, et al. Atypical chemokine receptor 3 induces colorectal tumorigenesis in mice by promoting β-arrestin-NOLC1-fibrillarin-dependent rRNA biogenesis[J]. Acta Pharmacol Sin, 2022, 43(11): 2967-2976. DOI: 10.1038/s41401-022-00901-x.

[44] SI M, SONG Y, WANG X, et al. CXCL12/CXCR7/β-arrestin1 biased signal promotes epithelial-to-mesenchymal transition of colorectal cancer by repressing miRNAs through YAP1 nuclear translocation[J]. Cell Biosci, 2022, 12(1): 171. DOI: 10.1186/s13578-022-00908-1.

[45] WANG G, PANG Y, LI N, et al. CXCR7 promoted proliferation, migration and invasion in HCC cells by inactivating Hippo-YAP signaling[J]. Discov Oncol, 2025, 16(1): 561. DOI: 10.1007/s12672-025-02324-6.

[46] FLORANOVIĆ M P, PETROVIĆ A R, VELIČKOVIĆ L J . Expression of the CXCR4 and CXCR7 in renal cancers; can “the orphan receptor” predict the mortality?[J]. Ann Diagn Pathol, 2021, 55: 151829. DOI: 10.1016/j.anndiagpath.2021.151829.

[47] GRITSINA G, FONG K W, LU X, et al. Chemokine receptor CXCR7 activates Aurora Kinase A and promotes neuroendocrine prostate cancer growth[J]. J Clin Invest, 2023, 133(15): e166248. DOI: 10.1172/JCI166248.

[48] GRITSINA G, YU J . CXCR7 as a novel therapeutic target for advanced prostate cancer[J]. Oncogene, 2023, 42(11): 785-792. DOI: 10.1038/s41388-023-02597-7.

[49] ISCI D, KUPPENS A, SCALISI J, et al. Heterogeneous expression of the atypical chemokine receptor ACKR3 in glioblastoma patient-derived tissue samples and cell cultures[J]. Sci Rep, 2024, 14(1): 21925. DOI: 10.1038/s41598-024-73064-w.

[50] BOBKOV V, ARIMONT M, ZARCA A, et al. Antibodies targeting chemokine receptors CXCR4 and ACKR3[J]. Mol Pharmacol, 2019, 96(6): 753-764. DOI: 10.1124/mol.119.116954.

[51] GUILLEMOT E, KARIMDJEE-SOILIHI B, PRADELLI E, et al. CXCR7 receptors facilitate the progression of colon carcinoma within lung not within liver[J]. Br J Cancer, 2012, 107(12): 1944-1949. DOI: 10.1038/bjc.2012.503.

[52] HUYNH C, HENRICH A, STRASSER D S, et al. A multipurpose first-in-human study with the novel CXCR7 antagonist ACT-1004-1239 using CXCL12 plasma concentrations as target engagement biomarker[J]. Clin Pharmacol Ther, 2021, 109(6): 1648-1659. DOI: 10.1002/cpt.2154.

[53] SCHLIMGEN R R, PETERSON F C, HEUKERS R, et al. Structural basis for selectivity and antagonism in extracellular GPCR-nanobodies[J]. Nat Commun, 2024, 15(1): 4611. DOI: 10.1038/s41467-024-49000-x.

[54] LIU C C, YANG W B, CHIEN C H, et al. CXCR7 activation evokes the anti-PD-L1 antibody against glioblastoma by remodeling CXCL12-mediated immunity[J]. Cell Death Dis, 2024, 15(6): 434. DOI: 10.1038/s41419-024-06784-6.

[55] MIN H Y, LEE H Y . Molecular targeted therapy for anticancer treatment[J]. Exp Mol Med, 2022, 54(10): 1670-1694. DOI: 10.1038/s12276-022-00864-3.

基金资助

国家自然科学基金地区基金项目(82360467)

贵州省科技厅基金项目(黔科合基础-ZK[2023]一般 358)

贵州省卫生健康委科学技术基金项目(gzwkj2023-282)