{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T20:28:18Z","timestamp":1792787298573,"version":"4.5.0"},"reference-count":49,"publisher":"BMJ","issue":"7","license":[{"start":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T00:00:00Z","timestamp":1785283200000},"content-version":"unspecified","delay-in-days":28,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100021171","name":"Basic and Applied Basic Research Foundation of Guangdong Province","doi-asserted-by":"publisher","award":["2024A1515013090"],"award-info":[{"award-number":["2024A1515013090"]}],"id":[{"id":"10.13039\/501100021171","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81860454"],"award-info":[{"award-number":["81860454"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82260500"],"award-info":[{"award-number":["82260500"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Guangdong Science and Technology Department","award":["2024B1212030002"],"award-info":[{"award-number":["2024B1212030002"]}],"id":[{"id":"https:\/\/ror.org\/00tjzgn92","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Key Research and Development Program Project of Liaoning Province","award":["2025JH2\/101800396"],"award-info":[{"award-number":["2025JH2\/101800396"]}]},{"name":"Liaoning Provincial Science and Technology Plan Joint Program Key R&D Project","award":["1210725033"],"award-info":[{"award-number":["1210725033"]}]},{"DOI":"10.13039\/501100007129","name":"Natural Science Foundation of Shandong Province","doi-asserted-by":"publisher","award":["ZR2023QH010"],"award-info":[{"award-number":["ZR2023QH010"]}],"id":[{"id":"10.13039\/501100007129","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002858","name":"China Postdoctoral Science Foundation","doi-asserted-by":"publisher","award":["2021M700949"],"award-info":[{"award-number":["2021M700949"]}],"id":[{"id":"10.13039\/501100002858","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2026,7,11]]},"published-print":{"date-parts":[[2026,7]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Neuroendocrine prostate cancer (NEPC) is characterized by strong immune evasion and profound metabolic reprogramming. A high regulatory T cell (Treg)\/CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cell ratio and an increased proportion of M2\/M1 tumor-associated macrophages (TAMs) in the NEPC tumor microenvironment (TME) are associated with poorer progression-free survival, a phenomenon linked to lipid accumulation within the TME. Understanding the regulatory mechanisms governing both the metabolic and immune landscapes of NEPC is critical.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>To investigate these mechanisms, prostate cancer cell lines and patient samples were analyzed using immunohistochemistry, flow cytometry, PCR, western blotting, and mass spectrometry. The interleukin (IL)-8\/CXCR2 signaling pathway was targeted for intervention in two tumor-bearing mouse models.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Data revealed that IL-8\/CXCR2 signaling drives the accumulation of free fatty acids and very-long-chain polyunsaturated fatty acids, leading to ferroptosis in tumor-infiltrating CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells. This, in turn, promotes Treg cell infiltration and an M2 macrophage-dominant immune landscape. Mechanistically, IL-8\/CXCR2 signaling upregulates the AKT-mTOR-FAS pathway while activating the mTOR-MYC-ELOVL5 axis via Rictor acetylation. In preclinical studies using NSG and B57BL\/6 mouse models, CXCR2 inhibition restored CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cell antitumor activity and enhanced TAM phagocytosis, significantly reducing tumor growth.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>These findings highlight CXCR2 as a promising immunotherapeutic target for NEPC and underscore its relevance in translational medicine.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/jitc-2025-014725","type":"journal-article","created":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T11:10:29Z","timestamp":1785323429000},"page":"e014725","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"title":["CXCR2-mediated metabolic interaction between prostate cancer cells and the immunosuppressive tumor microenvironment"],"prefix":"10.1136","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8688-4879","authenticated-orcid":false,"given":"Yi","family":"Sun","sequence":"first","affiliation":[{"name":"Urology, Guangzhou Medical University, Guangzhou, Guangdong, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Jing","sequence":"additional","affiliation":[{"name":"Department of Rheumatology and Clinical Immunology, Shenshan Medical Center, Sun Yat-Sen Memorial Hospital, Shanwei, Guangdong, China"},{"name":"Guangdong Provincial Key Laboratory of Cancer Pathogenesis and Precision Diagnosis and Treatment, Shenshan Medical Center, Sun Yat-Sen Memorial Hospital, Shanwei, Guangdong, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shangqing","family":"Ren","sequence":"additional","affiliation":[{"name":"Robotic Minimally Invasive Surgery Center, Sichuan Provincial People\u2019s Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xu","family":"Luo","sequence":"additional","affiliation":[{"name":"Department of Urology, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, Sichuan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Wen","sequence":"additional","affiliation":[{"name":"Department of Urology, West China Tianfu Hospital, Sichuan University, Chengdu, Sichuan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Jin","sequence":"additional","affiliation":[{"name":"Department of Urology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China"},{"name":"Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, The Second Xiangya Hospital of Central South University National Clinical Research Center for Metabolic Diseases, Changsha, Hunan, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guohua","family":"Zeng","sequence":"additional","affiliation":[{"name":"Guangzhou Medical University, Guangzhou, Guangdong, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuewen","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Urology, Qilu Hospital of Shandong University, Jinan, Shandong, China"},{"name":"Key Laboratory of Urinary Precision Diagnosis and Treatment in Universities of Shandong, Shandong Provincial Engineering Research Center for Precision Diagnosis and Treatment of Urological and Male Reproductive Diseases, Jinan, Shandong, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mo","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Urology, The First Hospital of China Medical University, Shenyang, Liaoning, China"},{"name":"Institute of Urology, China Medical University, Shenyang, Liaoning, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-0881-0936","authenticated-orcid":false,"given":"Ju","family":"Guo","sequence":"additional","affiliation":[{"name":"Department of Urology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China"},{"name":"Jiangxi Provincial Key Laboratory of Urinary System Diseases, Nanchang, Jiangxi, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2026,7,29]]},"reference":[{"key":"2026091704251961000_14.7.e014725.1","doi-asserted-by":"publisher","DOI":"10.1038\/s41585-021-00490-0"},{"key":"2026091704251961000_14.7.e014725.2","doi-asserted-by":"crossref","DOI":"10.1126\/scitranslmed.aax0428","article-title":"Targeting cellular heterogeneity with CXCR2 blockade for the treatment of therapy-resistant prostate cancer","volume":"11","author":"Li","year":"2019","journal-title":"Sci Transl Med"},{"key":"2026091704251961000_14.7.e014725.3","doi-asserted-by":"crossref","first-page":"113424","DOI":"10.1016\/j.celrep.2023.113424","article-title":"Prostate cancer cell-derived exosomal IL-8 fosters immune evasion by disturbing glucolipid metabolism of CD8+ T cell","volume":"42","author":"Xu","year":"2023","journal-title":"Cell Rep"},{"key":"2026091704251961000_14.7.e014725.4","doi-asserted-by":"crossref","first-page":"803","DOI":"10.1038\/s43018-021-00227-3","article-title":"Castration-mediated IL-8 promotes myeloid infiltration and prostate cancer progression","volume":"2","author":"Lopez-Bujanda","year":"2021","journal-title":"Nat Cancer"},{"key":"2026091704251961000_14.7.e014725.5","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9440(10)62490-X"},{"key":"2026091704251961000_14.7.e014725.6","doi-asserted-by":"publisher","DOI":"10.1016\/j.pharmthera.2008.10.005"},{"key":"2026091704251961000_14.7.e014725.7","doi-asserted-by":"publisher","DOI":"10.7150\/thno.15625"},{"key":"2026091704251961000_14.7.e014725.8","doi-asserted-by":"publisher","DOI":"10.1158\/1541-7786.MCR-19-0595"},{"key":"2026091704251961000_14.7.e014725.9","doi-asserted-by":"crossref","DOI":"10.1136\/jitc-2020-002138","article-title":"N-cadherin inhibitor creates a microenvironment that protect TILs from immune checkpoints and Treg cells","volume":"9","author":"Sun","year":"2021","journal-title":"J Immunother Cancer"},{"key":"2026091704251961000_14.7.e014725.10","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2020.06.016"},{"key":"2026091704251961000_14.7.e014725.11","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2021.02.015"},{"key":"2026091704251961000_14.7.e014725.12","doi-asserted-by":"crossref","DOI":"10.1038\/s41467-020-15296-8","article-title":"Olfactory specificity regulates lipid metabolism through neuroendocrine signaling in Caenorhabditis elegans","volume":"11","author":"Mutlu","year":"2020","journal-title":"Nat Commun"},{"key":"2026091704251961000_14.7.e014725.13","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-20-2808"},{"key":"2026091704251961000_14.7.e014725.14","doi-asserted-by":"crossref","first-page":"914","DOI":"10.1038\/s42255-024-01037-4","article-title":"Acetate reprogrammes tumour metabolism and promotes PD-L1 expression and immune evasion by upregulating c-Myc","volume":"6","author":"Wang","year":"2024","journal-title":"Nat Metab"},{"key":"2026091704251961000_14.7.e014725.15","doi-asserted-by":"crossref","DOI":"10.1186\/s12943-025-02436-1","article-title":"Targeting CXCR2 in prostate cancer cells can block CD47-SIRP\u03b1 interaction and reverse M2 macrophage polarization in the TME","volume":"24","author":"Sun","year":"2025","journal-title":"Mol Cancer"},{"key":"2026091704251961000_14.7.e014725.16","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.Can-21-0914"},{"key":"2026091704251961000_14.7.e014725.17","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1603244113"},{"key":"2026091704251961000_14.7.e014725.18","doi-asserted-by":"crossref","DOI":"10.1084\/jem.20191920","article-title":"Accumulation of long-chain fatty acids in the tumor microenvironment drives dysfunction in intrapancreatic CD8+ T cells","volume":"217","author":"Manzo","year":"2020","journal-title":"J Exp Med"},{"key":"2026091704251961000_14.7.e014725.19","doi-asserted-by":"crossref","first-page":"3957","DOI":"10.3390\/cancers13163957","article-title":"ELOVL5-Mediated Long Chain Fatty Acid Elongation Contributes to Enzalutamide Resistance of Prostate Cancer","volume":"13","author":"Xu","year":"2021","journal-title":"Cancers (Basel)"},{"key":"2026091704251961000_14.7.e014725.20","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2019.07.012"},{"key":"2026091704251961000_14.7.e014725.21","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2024.08.015"},{"key":"2026091704251961000_14.7.e014725.22","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0706832104"},{"key":"2026091704251961000_14.7.e014725.23","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbagen.2012.11.020"},{"key":"2026091704251961000_14.7.e014725.24","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2013.09.013"},{"key":"2026091704251961000_14.7.e014725.25","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2013.04.013"},{"key":"2026091704251961000_14.7.e014725.26","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2012.03.003"},{"key":"2026091704251961000_14.7.e014725.27","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2010.10.019"},{"key":"2026091704251961000_14.7.e014725.28","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1511759112"},{"key":"2026091704251961000_14.7.e014725.29","doi-asserted-by":"publisher","DOI":"10.1038\/s41422-024-00985-6"},{"key":"2026091704251961000_14.7.e014725.30","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2015.05.014"},{"key":"2026091704251961000_14.7.e014725.31","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2019.06.001"},{"key":"2026091704251961000_14.7.e014725.32","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2021.04.001"},{"key":"2026091704251961000_14.7.e014725.33","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2682-1"},{"key":"2026091704251961000_14.7.e014725.34","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2022.12.008"},{"key":"2026091704251961000_14.7.e014725.35","doi-asserted-by":"crossref","first-page":"969","DOI":"10.1016\/j.cmet.2024.02.009","article-title":"Acetyl-CoA carboxylase obstructs CD8+ T cell lipid utilization in the tumor microenvironment","volume":"36","author":"Hunt","year":"2024","journal-title":"Cell Metab"},{"key":"2026091704251961000_14.7.e014725.36","doi-asserted-by":"publisher","DOI":"10.1016\/j.tcb.2023.05.003"},{"key":"2026091704251961000_14.7.e014725.37","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2017.09.021"},{"key":"2026091704251961000_14.7.e014725.38","doi-asserted-by":"crossref","first-page":"741","DOI":"10.1038\/s42255-024-01019-6","article-title":"Fatty acid binding protein 5 suppression attenuates obesity-induced hepatocellular carcinoma by promoting ferroptosis and intratumoral immune rewiring","volume":"6","author":"Sun","year":"2024","journal-title":"Nat Metab"},{"key":"2026091704251961000_14.7.e014725.39","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1111\/imr.13235","article-title":"Ferroptosis in immunostimulation and immunosuppression","volume":"321","author":"Tang","year":"2024","journal-title":"Immunol Rev"},{"key":"2026091704251961000_14.7.e014725.40","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2024.03.015"},{"key":"2026091704251961000_14.7.e014725.41","doi-asserted-by":"crossref","DOI":"10.1136\/jitc-2023-008662","article-title":"CD276 regulates the immune escape of esophageal squamous cell carcinoma through CXCL1-CXCR2 induced NETs","volume":"12","author":"Xiong","year":"2024","journal-title":"J Immunother Cancer"},{"key":"2026091704251961000_14.7.e014725.42","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-024-01914-4"},{"key":"2026091704251961000_14.7.e014725.43","doi-asserted-by":"crossref","first-page":"1972","DOI":"10.1016\/j.ccell.2023.10.006","article-title":"Anti-PD-1 immunotherapy with androgen deprivation therapy induces robust immune infiltration in metastatic castration-sensitive prostate cancer","volume":"41","author":"Hawley","year":"2023","journal-title":"Cancer Cell"},{"key":"2026091704251961000_14.7.e014725.44","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-023-06255-6"},{"key":"2026091704251961000_14.7.e014725.45","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2024.03.019"},{"key":"2026091704251961000_14.7.e014725.46","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2018.06.039"},{"key":"2026091704251961000_14.7.e014725.47","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2017.77.6880"},{"key":"2026091704251961000_14.7.e014725.48","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-024-01826-3"},{"key":"2026091704251961000_14.7.e014725.49","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2006828117"}],"container-title":["Journal for ImmunoTherapy of Cancer"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/jitc-2025-014725","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T11:25:30Z","timestamp":1789644330000},"score":1,"resource":{"primary":{"URL":"https:\/\/jitc.bmj.com\/lookup\/doi\/10.1136\/jitc-2025-014725"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7]]},"references-count":49,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2026,7,29]]},"published-print":{"date-parts":[[2026,7]]}},"alternative-id":["10.1136\/jitc-2025-014725"],"URL":"https:\/\/doi.org\/10.1136\/jitc-2025-014725","relation":{},"ISSN":["2051-1426"],"issn-type":[{"value":"2051-1426","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7]]}}}