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Maxwell 1, Cristina Branco 1, Simon T. Barry 2, Cath Eberlein 2 and Melissa J. LaBonte 1, *  \nCitation: McClelland, S.; Maxwell, P.J.; Branco, C.; Barry, S.T.; Eberlein, C.; LaBonte, M.J. Targeting IL-8 and Its Receptors in Prostate Cancer:  \nInflammation, Stress Response, and Treatment Resistance. Cancers 2024, 16, 2797. [https://doi.org/10.3390/](https://doi.org/10.3390/)[ ](https://doi.org/10.3390/)cancers16162797  \nAcademic Editor: Zaklina Kovacevic  \nReceived: 1 July 2024  \nRevised: 30 July 2024  \nAccepted: 5 August 2024  \nPublished: 8 August 2024  \nCopyright: © 2024 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ([https://](https://)[ ](https://)[creativecommons.org/licenses/by/](creativecommons.org/licenses/by/)[ ](creativecommons.org/licenses/by/)[4.0/](4.0/)) .  \n1 Patrick G Johnston Centre for Cancer Research, School of Medicine, Dentistry and Biomedical Sciences, Queen’s University Belfast, 97 Lisburn Road, Belfast BT9 7AE, UK; [smcclelland11@qub.ac.uk](smcclelland11@qub.ac.uk) (S.M.); [pamela.maxwell@qub.ac.uk](pamela.maxwell@qub.ac.uk) (P.J.M.); [c.branco@qub.ac.uk](c.branco@qub.ac.uk) (C.B.)  \n2 Bioscience Early Oncology, AstraZeneca, Cambridge CB2 0AA, UK; [simon.t.barry@astrazeneca.com](simon.t.barry@astrazeneca.com) (S.T.B.); [cath.eberlein1@astrazeneca.com](cath.eberlein1@astrazeneca.com) (C.E.)  \n* [Correspondence: m.labontewilson@qub.ac.uk](Correspondence: m.labontewilson@qub.ac.uk); Tel.: +44-2890972789  \nSimple Summary: Prostate cancer remains a significant health issue, particularly when it progresses to castration-resistant (CRPC) and metastatic CRPC (mCRPC) . This review explores the role of interleukin-8 (IL-8) and its receptors, CXCR1 and CXCR2, in prostate cancer. IL-8 remains a key player in inflammation and tumour growth, promoting cancer cell survival, migration, and resistance to therapies. By targeting IL-8 signalling, researchers aim to develop new treatments that can enhance the effectiveness of existing therapies and improve outcomes for patients with resistant forms of prostate cancer. This approach could lead to better management of the disease and provide new hope for patients facing limited treatment options.  \nAbstract: This review delves into the intricate roles of interleukin-8 (IL-8) and its receptors, CXCR1 and CXCR2, in prostate cancer (PCa), particularly in castration-resistant (CRPC) and metastatic CRPC (mCRPC) . This review emphasizes the crucial role of the tumour microenvironment (TME) and inflammatory cytokines in promoting tumour progression and response to tumour cell targeting agents. IL-8, acting through C-X-C chemokine receptor type 1 (CXCR1) and type 2 (CXCR2), modulates multiple signalling pathways, enhancing the angiogenesis, proliferation, and migration of cancer cells. This review highlights the shift in PCa research focus from solely tumour cells to the non-cancer-cell components, including vascular endothelial cells, the extracellular matrix, immune cells, and the dynamic interactions within the TME. The immunosuppressive nature of the PCa TME significantly influences tumour progression and resistance to emerging therapies. Current treatment modalities, including androgen deprivation therapy and chemotherapeutics, encounter persistent resistance and are complicated by prostate cancer’s notably “immune-cold” nature, which limits immune system response to the tumour. These challenges underscore the critical need for novel approaches that both overcome resistance and enhance immune engagement within the TME. The therapeutic potential of inhibiting IL-8 signalling is explored, with studies showing enhanced sensitivity of PCa cells to treatments, including radiation and an","cbCainemj5n4nkHu","https://ap.wps.com/l/cbCainemj5n4nkHu","pdf",3091811,25,"English","# Introduction\n## IL-8 signaling in prostate cancer\n## Tumour microenvironment and inflammatory cytokines\n## Therapeutic resistance and immune-cold biology\n## Targeting IL-8 pathways and CXCR2-based combinations","[{\"question\":\"What role does IL-8 play in prostate cancer progression?\",\"answer\":\"IL-8 promotes inflammation and tumour growth, supporting cancer cell survival, migration, and resistance to therapies. It also contributes to angiogenesis, proliferation, and signalling changes within the tumour microenvironment.\"},{\"question\":\"Which receptors are highlighted as key IL-8 mediators?\",\"answer\":\"The review emphasizes IL-8 receptors CXCR1 and CXCR2. These receptors modulate multiple signalling pathways that influence tumour behaviour.\"},{\"question\":\"How does targeting IL-8 signalling relate to treatment resistance and immune response?\",\"answer\":\"The article links IL-8-driven biology to persistent resistance seen with current therapies. It also addresses the immune-cold nature of the tumour microenvironment, motivating IL-8 pathway inhibition to improve immune engagement and therapeutic sensitivity.\"}]","Targeting IL-8 and Its Receptors in Prostate Cancer - Inflammation, Stress Response, and Treatment Resistance | PDF",1789980501,63]