{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T22:13:50Z","timestamp":1790633630654,"version":"4.1.0"},"reference-count":44,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T00:00:00Z","timestamp":1787184000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>The role of neutrophil extracellular traps (NETs) in cervical cancer (CC) progression, particularly their association with human papillomavirus (HPV) infection, remains unclear.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We analyzed public single-cell RNA sequencing data to explore neutrophil heterogeneity in the HPV-associated CC microenvironment and quantitatively assessed NETs in clinical tissues and serum from normal subjects, HPV-negative, and HPV-positive CC patients.\n                      <jats:italic>In vitro<\/jats:italic>\n                      , CC cell lines and normal epithelial cells were treated with neutrophil-conditioned medium, followed by phenotypic evaluation using EdU, Transwell, and vasculogenic formation assays.\n                      <jats:italic>In vivo<\/jats:italic>\n                      validation was conducted using subcutaneous xenograft and tail-vein metastasis models. Potential mechanisms of HPV-regulated NETs formation were further investigated through co-culture, immunoblotting, and ROS detection.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Single-cell transcriptomic analysis revealed a characteristic neutrophil subpopulation (N4) in HPV-positive tumor microenvironments, whose gene expression signature is highly correlated with NETs formation capability. NETs were elevated in CC tissues and sera, especially in HPV-positive tumors. High tissue levels of the NETs-specific marker Cit-H3 correlated with larger tumor diameter, deep stromal invasion and poor differentiation. Functionally, NETs promoted proliferation, angiogenesis, invasion and migration of CC cells;\n                      <jats:italic>in vivo<\/jats:italic>\n                      , experiments showed NETs drove tumor growth and pulmonary metastasis, effects abolished by DNase 1-mediated NETs degradation. Mechanistically, HPV-positive cancer cells secrete substantial amounts of CXCL8, which activates CXCR1\/2 receptors, thereby inducing reactive oxygen species production and p21 upregulation to drive neutrophil extracellular trap formation. Targeting this axis reversed NETs generation.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>The HPV-triggered CXCL8-CXCR1\/2-ROS-p21 pathway drives NETs formation that accelerates CC growth and metastasis. Circulating NETs represent a potential prognostic biomarker.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1861481","type":"journal-article","created":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T05:26:25Z","timestamp":1787203585000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Elevated neutrophil extracellular traps formation driven by the HPV-mediated CXCL8-CXCR1\/2-ROS-p21 axis promotes the growth and metastasis of cervical cancer"],"prefix":"10.3389","volume":"17","author":[{"given":"Xin","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Pathology, Basic Medical College, Xinjiang Medical University","place":["Urumqi, Xinjiang, China"]},{"name":"Department of Pathology, Urumqi Friendship Hospital","place":["Urumqi, Xinjiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alimire","family":"Julaiti","sequence":"additional","affiliation":[{"name":"Department of Pathology, Basic Medical College, Xinjiang Medical University","place":["Urumqi, Xinjiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aikelimu","family":"Aisikaer","sequence":"additional","affiliation":[{"name":"Department of Pathology, Basic Medical College, Xinjiang Medical University","place":["Urumqi, Xinjiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongjian","family":"Wei","sequence":"additional","affiliation":[{"name":"Department of Pathology, Urumqi Friendship Hospital","place":["Urumqi, Xinjiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Runda","family":"Jie","sequence":"additional","affiliation":[{"name":"Department of Pathology, Basic Medical College, Xinjiang Medical University","place":["Urumqi, Xinjiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyan","family":"Liu","sequence":"additional","affiliation":[{"name":"Clinical Medicine Department, Xinjiang Medical University","place":["Urumqi, Xinjiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yonghua","family":"Shi","sequence":"additional","affiliation":[{"name":"Department of Pathology, Basic Medical College, Xinjiang Medical University","place":["Urumqi, Xinjiang, China"]},{"name":"Xinjiang Key Laboratory of Molecular Biology for Endemic Diseases","place":["Urumqi, Xinjiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,20]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"12","DOI":"10.3322\/caac.21820","article-title":"Cancer statistics, 2024","volume":"74","author":"Siegel","year":"2024","journal-title":"CA Cancer J Clin"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1097\/01.ogx.0001004660.29812.17","article-title":"Cervical cancer screening: a review","volume":"330","author":"Perkins","year":"2023","journal-title":"Jama"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1002\/jmv.70564","article-title":"Role of NTRK fusion genes in the tumor immune microenvironment of HPV (+\/-) cervical cancer","volume":"97","author":"Wang","year":"2025","journal-title":"J Med Virol"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/j.canlet.2020.10.034","article-title":"HPV post-infection microenvironment and cervical cancer","volume":"497","author":"Yuan","year":"2021","journal-title":"Cancer Lett"},{"key":"B5","doi-asserted-by":"publisher","first-page":"260","DOI":"10.1186\/s13046-020-01745-1","article-title":"Extracellular vesicular Wnt7b mediates HPV E6-induced cervical cancer angiogenesis by activating the \u03b2-catenin signaling pathway","volume":"39","author":"Qiu","year":"2020","journal-title":"J Exp Clin Cancer Res"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbcan.2022.188762","article-title":"Tumor-associated neutrophils and neutrophil-targeted cancer therapies","volume":"1877","author":"Que","year":"2022","journal-title":"Biochim Biophys Acta Rev Cancer"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-021-00571-6","article-title":"Neutrophils in cancer: heterogeneous and multifaceted","volume":"22","author":"Hedrick","year":"2022","journal-title":"Nat Rev Immunol"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-022-05400-x","article-title":"Liver tumour immune microenvironment subtypes and neutrophil heterogeneity","volume":"612","author":"Xue","year":"2022","journal-title":"Nature"},{"key":"B9","doi-asserted-by":"publisher","first-page":"233","DOI":"10.1186\/s13046-021-02013-6","article-title":"Neutrophil extracellular traps: a new player in cancer metastasis and therapeutic target","volume":"40","author":"Yang","year":"2021","journal-title":"J Exp Clin Cancer Res"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2023.02.001","article-title":"NETworking with cancer: the bidirectional interplay between cancer and neutrophil extracellular traps","volume":"41","author":"Adrover","year":"2023","journal-title":"Cancer Cell"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1126\/science.1092385","article-title":"Neutrophil extracellular traps kill bacteria","volume":"303","author":"Brinkmann","year":"2004","journal-title":"Science"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1016\/j.canlet.2024.217288","article-title":"S100A7 orchestrates neutrophil chemotaxis and drives neutrophil extracellular traps (NETs) formation to facilitate lymph node metastasis in cervical cancer patients","volume":"605","author":"Ning","year":"2024","journal-title":"Cancer Lett"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1016\/j.intimp.2023.110330","article-title":"The role of CXCL1\/CXCR2 axis in neurological diseases","volume":"120","author":"Jiang","year":"2023","journal-title":"Int Immunopharmacol"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1038\/s41423-023-00974-6","article-title":"The chemokines CXCL8 and CXCL12: molecular and functional properties, role in disease and efforts towards pharmacological intervention","volume":"20","author":"Cambier","year":"2023","journal-title":"Cell Mol Immunol"},{"key":"B15","doi-asserted-by":"publisher","first-page":"190","DOI":"10.1002\/path.5753","article-title":"Heterogenous presence of neutrophil extracellular traps in human solid tumours is partially dependent on IL-8","volume":"255","author":"de Andrea","year":"2021","journal-title":"J Pathol"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1016\/j.chest.2022.06.007","article-title":"Neutrophil extracellular traps, local IL-8 expression, and cytotoxic T-lymphocyte response in the lungs of patients with fatal COVID-19","volume":"162","author":"Melero","year":"2022","journal-title":"Chest"},{"key":"B17","doi-asserted-by":"publisher","first-page":"353","DOI":"10.3892\/etm.2021.9784","article-title":"Differentiation of HL-60 cells in serum-free hematopoietic cell media enhances the production of neutrophil extracellular traps","volume":"21","author":"Guo","year":"2021","journal-title":"Exp Ther Med"},{"key":"B18","doi-asserted-by":"publisher","first-page":"1127","DOI":"10.3390\/biomedicines9091127","article-title":"The Fc\u03b3RIII engagement augments PMA-stimulated neutrophil extracellular traps (NETs) formation by granulocytes partially via cross-talk between Syk-ERK-NF-\u03baB and PKC-ROS signaling pathways","volume":"9","author":"Lu","year":"2021","journal-title":"Biomedicines"},{"key":"B19","doi-asserted-by":"publisher","first-page":"289","DOI":"10.1111\/j.1600-0609.1987.tb00001.x","article-title":"Retinoic acid-induced differentiation of the human promyelocytic leukemia cell line, HL-60, and fresh human leukemia cells in primary culture: a model for differentiation inducing therapy of leukemia","volume":"38","author":"Imaizumi","year":"1987","journal-title":"Eur J Haematol"},{"key":"B20","doi-asserted-by":"publisher","first-page":"441","DOI":"10.21037\/atm.2020.03.190","article-title":"Preoperative leukocytosis is associated with increased tumor-infiltrating neutrophil extracellular traps and worse outcomes in esophageal cancer","volume":"8","author":"Zhang","year":"2020","journal-title":"Ann Transl Med"},{"key":"B21","doi-asserted-by":"publisher","first-page":"1118","DOI":"10.3390\/ijms24021118","article-title":"Neutrophil extracellular traps promote metastases of colorectal cancers through activation of ERK signaling by releasing neutrophil elastase","volume":"24","author":"Okamoto","year":"2023","journal-title":"Int J Mol Sci"},{"key":"B22","doi-asserted-by":"publisher","first-page":"277","DOI":"10.1152\/physrev.00062.2021","article-title":"Neutrophil extracellular traps in the pathology of cancer and other inflammatory diseases","volume":"103","author":"Herre","year":"2023","journal-title":"Physiol Rev"},{"key":"B23","doi-asserted-by":"publisher","first-page":"235","DOI":"10.1038\/s41392-024-01933-x","article-title":"Neutrophil extracellular traps in homeostasis and disease","volume":"9","author":"Wang","year":"2024","journal-title":"Signal Transduct Tgt Ther"},{"key":"B24","doi-asserted-by":"publisher","first-page":"218","DOI":"10.1038\/s41419-024-06594-w","article-title":"TGF-\u03b2-driven LIF expression influences neutrophil extracellular traps (NETs) and contributes to peritoneal metastasis in gastric cancer","volume":"15","author":"Zhang","year":"2024","journal-title":"Cell Death Dis"},{"key":"B25","doi-asserted-by":"publisher","first-page":"236","DOI":"10.1186\/s13046-023-02817-8","article-title":"Fusobacterium nucleatum-triggered neutrophil extracellular traps facilitate colorectal carcinoma progression","volume":"42","author":"Kong","year":"2023","journal-title":"J Exp Clin Cancer Res"},{"key":"B26","doi-asserted-by":"publisher","first-page":"e009082","DOI":"10.1136\/jitc-2024-009082","article-title":"Tumor cell-released autophagosomes (TRAPs) induce PD-L1-decorated NETs that suppress T-cell function to promote breast cancer pulmonary metastasis","volume":"12","author":"Zhou","year":"2024","journal-title":"J Immunother Cancer"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.867516","article-title":"Neutrophil extracellular traps (NETs) promote non-small cell lung cancer metastasis by suppressing lncRNA MIR503HG to activate the NF-\u03baB\/NLRP3 inflammasome pathway","volume":"13","author":"Wang","year":"2022","journal-title":"Front Immunol"},{"key":"B28","doi-asserted-by":"publisher","first-page":"176","DOI":"10.1186\/s12964-023-01196-z","article-title":"Neutrophil extracellular traps promote angiogenesis in gastric cancer","volume":"21","author":"Yang","year":"2023","journal-title":"Cell Commun Signal"},{"key":"B29","doi-asserted-by":"publisher","first-page":"1542","DOI":"10.3390\/cancers12061542","article-title":"Neutrophil extracellular traps (NETs) promote pro-metastatic phenotype in human breast cancer cells through epithelial-mesenchymal transition","volume":"12","author":"Martins-Cardoso","year":"2020","journal-title":"Cancers (Bsl)"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1002\/path.5860","article-title":"Neutrophil extracellular traps drive epithelial-mesenchymal transition of human colon cancer","volume":"256","author":"Stehr","year":"2022","journal-title":"J Pathol"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.5582\/bst.2019.01326","article-title":"The pro-tumor effect and the anti-tumor effect of neutrophils extracellular traps","volume":"13","author":"Liu","year":"2020","journal-title":"Biosci Trends"},{"key":"B32","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1016\/j.semcancer.2021.07.011","article-title":"Neutrophil extracellular traps in cancer","volume":"79","author":"Cristinziano","year":"2022","journal-title":"Semin Cancer Biol"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2024.03.002","article-title":"DAMPs and DAMP-sensing receptors in inflammation and diseases","volume":"57","author":"Ma","year":"2024","journal-title":"Immunity"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1093\/jleuko\/qiae166","article-title":"G-CSF induces neutrophil extracellular traps formation and promotes ovarian cancer peritoneal dissemination","volume":"116","author":"Bun","year":"2024","journal-title":"J Leukoc Biol"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.20892\/j.issn.2095-3941.2019.0353","article-title":"Neutrophil extracellular traps mediate the crosstalk between glioma progression and the tumor microenvironment via the HMGB1\/RAGE\/IL-8 axis","volume":"17","author":"Zha","year":"2020","journal-title":"Cancer Biol Med"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1016\/j.mocell.2024.100113","article-title":"The role of p21 in cellular senescence and aging-related diseases","volume":"47","author":"Yan","year":"2024","journal-title":"Mol Cells"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1126\/science.abb3420","article-title":"p21 produces a bioactive secretome that places stressed cells under immunosurveillance","volume":"374","author":"Sturmlechner","year":"2021","journal-title":"Science"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1016\/j.redox.2024.103059","article-title":"A novel role for the ROS-ATM-Chk2 axis mediated metabolic and cell cycle reprogramming in the M1 macrophage polarization","volume":"70","author":"Li","year":"2024","journal-title":"Redox Biol"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1097\/ms9.0000000000002679","article-title":"From inflammation to invasion: neutrophils in cervical cancer pathogenesis","volume":"87","author":"Obeagu","year":"2025","journal-title":"Ann Med Surg (Lond)"},{"key":"B40","doi-asserted-by":"publisher","first-page":"36","DOI":"10.1186\/s12943-026-02570-4","article-title":"Spatiotemporal dynamics of tumor-associated neutrophils: bridging the gap between cancer progression and immunotherapy","volume":"25","author":"Chu","year":"2026","journal-title":"Mol Cancer"},{"key":"B41","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1111\/pcmr.12818","article-title":"Evidence and impact of neutrophil extracellular traps in Malignant melanoma","volume":"33","author":"Schedel","year":"2020","journal-title":"Pigment Cell Melanoma Res"},{"key":"B42","doi-asserted-by":"publisher","first-page":"1220","DOI":"10.3390\/biom15091220","article-title":"The dual role of macrophage extracellular traps in host defense and disease: mechanisms and therapeutic implications","volume":"15","author":"Chen","year":"2025","journal-title":"Biomolecules"},{"key":"B43","doi-asserted-by":"publisher","first-page":"293","DOI":"10.1007\/s12272-025-01540-6","article-title":"The dynamic roles of macrophages extracellular traps (METs) in immune regulation","volume":"48","author":"Shin","year":"2025","journal-title":"Arch Pharm Res"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1096\/fj.202400739r","article-title":"Emerging insights into macrophage extracellular traps in bacterial infections","volume":"38","author":"Baz","year":"2024","journal-title":"FASEB J"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1861481\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T05:26:27Z","timestamp":1787203587000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1861481\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,20]]},"references-count":44,"alternative-id":["10.3389\/fimmu.2026.1861481"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2026.1861481","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,20]]},"article-number":"1861481"}}