{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T13:56:21Z","timestamp":1784296581372,"version":"3.55.0"},"reference-count":74,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2026,1,28]],"date-time":"2026-01-28T00:00:00Z","timestamp":1769558400000},"content-version":"vor","delay-in-days":33,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Health Holland grants DC4Balance","award":["LSHM18056-SGF"],"award-info":[{"award-number":["LSHM18056-SGF"]}]},{"name":"ImmuneHealthSeed","award":["LSHM22042-SGF"],"award-info":[{"award-number":["LSHM22042-SGF"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,12,26]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Neutrophils have recently been demonstrated to play a variable role in cancer progression, likely due to adaptability to environmental signals that influence neutrophil phenotype and function. In the tumor microenvironment, tumor-derived prostaglandin E2 is well established as a major suppressor of immune cell function and facilitates tumor immune evasion. However, while prostaglandin E2 is widely regarded to signal through the E-prostanoid receptors type (EP) 2 and EP4 on neutrophils, the exact effects of targeting this axis therapeutically in the context of cancer remain largely unexplored. In this study, we investigated the effect of prostaglandin E2 signaling via EP2\/4 in human neutrophils using specific EP2 and EP4 antagonists. We report that countering EP2\/4 signaling yields an activated phenotype together with the acquisition of proinflammatory properties, including the augmented production of reactive oxygen species, enhanced phagocytosis, and increased production of IL-8. Given the phagocytic nature of neutrophils, we encapsulated EP2\/4 antagonists into poly (lactic-co-glycolic acid) nanoparticles for the tailored delivery of these antagonists. Importantly, nanoparticles achieved robust phenotypical and functional activation of healthy neutrophils as well as cancer patient-derived neutrophils exposed to tumor-derived prostaglandin E2. Together, these results identify the role of EP2\/4 in regulating activation of human neutrophils and illustrate the relevance of targeting this axis with nanoparticles in the context of cancer for the reactivation of tumor-exposed neutrophils. We propose that targeting this axis in neutrophils using nanoparticles can serve to attenuate tumor-induced suppression by steering them toward a proinflammatory state and thus potentially support antitumor immune responses.<\/jats:p>","DOI":"10.1093\/jleuko\/qiaf186","type":"journal-article","created":{"date-parts":[[2026,1,21]],"date-time":"2026-01-21T12:40:39Z","timestamp":1768999239000},"source":"Crossref","is-referenced-by-count":2,"title":["Countering tumor-derived PGE2-EP2\/4 signaling mediates neutrophil activation"],"prefix":"10.1093","volume":"118","author":[{"given":"Johanna","family":"B\u00f6dder","sequence":"first","affiliation":[{"name":"Department of Medical BioSciences, Radboud University Medical Center , Geert Grooteplein 26-28, 6525 GA Nijmegen ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-6575-8847","authenticated-orcid":false,"given":"Robbin","family":"Kramer","sequence":"additional","affiliation":[{"name":"Department of Medical BioSciences, Radboud University Medical Center , Geert Grooteplein 26-28, 6525 GA Nijmegen ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-3340-9670","authenticated-orcid":false,"given":"Julia","family":"Minnee","sequence":"additional","affiliation":[{"name":"Department of Medical BioSciences, Radboud University Medical Center , Geert Grooteplein 26-28, 6525 GA Nijmegen ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4915-1518","authenticated-orcid":false,"given":"Jorge","family":"Cuenca-Escalona","sequence":"additional","affiliation":[{"name":"Department of Medical BioSciences, Radboud University Medical Center , Geert Grooteplein 26-28, 6525 GA Nijmegen ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sharon","family":"Bootsman","sequence":"additional","affiliation":[{"name":"Department of Medical BioSciences, Radboud University Medical Center , Geert Grooteplein 26-28, 6525 GA Nijmegen ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan","family":"Fauerbach","sequence":"additional","affiliation":[{"name":"R&D Reagents, Chemical Biology Department, Miltenyi Biotec B.V. & Co. KG , Friedrich-Ebert-Stra\u00dfe 68, 51429 Bergisch Gladbach ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4431-985X","authenticated-orcid":false,"given":"Georgina","family":"Fl\u00f3rez-Grau","sequence":"additional","affiliation":[{"name":"Department of Medical BioSciences, Radboud University Medical Center , Geert Grooteplein 26-28, 6525 GA Nijmegen ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Esther C","family":"de Jong","sequence":"additional","affiliation":[{"name":"Department Experimental Immunology, Amsterdam UMC, Location AMC, Amsterdam Institute for Infection and Immunity , Meibergdreef 9, 1105 AZ Amsterdam ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8653-4040","authenticated-orcid":false,"given":"Jolanda M","family":"de Vries","sequence":"additional","affiliation":[{"name":"Department of Medical BioSciences, Radboud University Medical Center , Geert Grooteplein 26-28, 6525 GA Nijmegen ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,1,28]]},"reference":[{"key":"2026012811580104200_qiaf186-B1","doi-asserted-by":"publisher","first-page":"1223","DOI":"10.1152\/physrev.00012.2018","article-title":"The Neutrophil's role during health and disease","volume":"99","author":"Liew","year":"2019","journal-title":"Physiol Rev."},{"key":"2026012811580104200_qiaf186-B2","doi-asserted-by":"publisher","first-page":"431","DOI":"10.1038\/nrc.2016.52","article-title":"Neutrophils in cancer: neutral no more","volume":"16","author":"Coffelt","year":"2016","journal-title":"Nat Rev Cancer."},{"key":"2026012811580104200_qiaf186-B3","doi-asserted-by":"publisher","first-page":"173","DOI":"10.1186\/s13045-021-01187-y","article-title":"Neutrophils in cancer carcinogenesis and metastasis","volume":"14","author":"Xiong","year":"2021","journal-title":"J Hematol Oncol."},{"key":"2026012811580104200_qiaf186-B4","doi-asserted-by":"publisher","first-page":"405","DOI":"10.1007\/s10555-022-10024-8","article-title":"Mechanistic insights into the interplays between neutrophils and other immune cells in cancer development and progression","volume":"41","author":"Mahmud","year":"2022","journal-title":"Cancer Metastasis Rev."},{"key":"2026012811580104200_qiaf186-B5","doi-asserted-by":"publisher","first-page":"485","DOI":"10.1038\/s41568-020-0281-y","article-title":"Neutrophil diversity and plasticity in tumour progression and therapy","volume":"20","author":"Jaillon","year":"2020","journal-title":"Nat Rev Cancer."},{"key":"2026012811580104200_qiaf186-B6","doi-asserted-by":"publisher","first-page":"1146","DOI":"10.3389\/fonc.2019.01146","article-title":"Tumor associated neutrophils. 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