{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T05:52:04Z","timestamp":1791525124667,"version":"4.3.4"},"reference-count":48,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T00:00:00Z","timestamp":1791504000000},"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:p>Cancer-associated fibroblasts (CAFs) are key regulators of the tumor microenvironment; however, their role in modulating neutrophil function during cervical cancer (CC) progression remains poorly understood. In this study, we evaluated whether CAF supernatants (CSN) derived from early (FIGO I\u2013II) and late stages (FIGO III\u2013IV) of CC differentially regulate neutrophil activity. Peripheral blood neutrophils from healthy donors were stimulated with CSN, and their functional responses were assessed, including cytokine production, metabolic activity (MTT), reactive oxygen species (ROS) generation, apoptosis and survival analyses, expression of activation (CD66b) and protease degranulation markers (MMP9 and NE), and neutrophil extracellular trap (NET) release. CSN factors promoted a predominantly proinflammatory cytokine profile in neutrophils, characterized by increased production of IL-6, IL-8, TNF-\u03b1, and IFN-\u03b3. Additionally, stimulation with CAF enhanced neutrophil metabolic activity, ROS production, survival, and expression of CD66b, MMP9, and neutrophil elastase, suggesting preliminary stage-associated differences in neutrophils responses between CAFs derived from early- and late-stage tumors. Notably, NET formation was significantly higher in neutrophils stimulated with early-stage CAFs, whereas late-stage CAFs induced a metabolically active but lower NETosis release. These exploratory findings suggest that cervical cancer-derived CAFs may differentially modulate neutrophil functional responses according to tumor stage, highlighting the CAF-neutrophil axis as a potentially relevant component of the cervical cancer microenvironment.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1900567","type":"journal-article","created":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T05:34:37Z","timestamp":1791524077000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Cancer-associated fibroblasts from cervical cancer modulate protumoral neutrophil functions: evidence from a pilot exploratory study"],"prefix":"10.3389","volume":"17","author":[{"given":"Luis Javier","family":"Res\u00e9ndiz-Castillo","sequence":"first","affiliation":[{"name":"Universidad de Guadalajara, Centro Universitario de Ciencias de la Salud, Departamento de Microbiolog\u00eda y Patolog\u00eda, Instituto de Investigaci\u00f3n en C\u00e1ncer e Infecciones","place":["Guadalajara, Jalisco, Mexico"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcela Guadalupe","family":"Mart\u00ednez-Barajas","sequence":"additional","affiliation":[{"name":"Universidad de Guadalajara, Centro Universitario de Ciencias de la Salud, Departamento de Microbiolog\u00eda y Patolog\u00eda, Instituto de Investigaci\u00f3n en C\u00e1ncer e Infecciones","place":["Guadalajara, Jalisco, Mexico"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahtziri Socorro","family":"Carranza-Aranda","sequence":"additional","affiliation":[{"name":"Universidad de Guadalajara, Centro Universitario de Ciencias de la Salud, Departamento de Disciplinas Filos\u00f3ficas, Metodol\u00f3gicas e Instrumentales","place":["Guadalajara, Jalisco, Mexico"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan Ren\u00e9","family":"Garc\u00eda-Bernal","sequence":"additional","affiliation":[{"name":"Universidad de Guadalajara, Centro Universitario de Ciencias de la Salud, Departamento de Microbiolog\u00eda y Patolog\u00eda, Instituto de Investigaci\u00f3n en C\u00e1ncer e Infecciones","place":["Guadalajara, Jalisco, Mexico"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlos Daniel","family":"D\u00edaz-Palomera","sequence":"additional","affiliation":[{"name":"Universidad de Guadalajara, Centro Universitario de Ciencias de la Salud, Departamento de Microbiolog\u00eda y Patolog\u00eda, Instituto de Investigaci\u00f3n en C\u00e1ncer e Infecciones","place":["Guadalajara, Jalisco, Mexico"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adri\u00e1n","family":"Ram\u00edrez-de-Arellano","sequence":"additional","affiliation":[{"name":"Universidad de Guadalajara, Centro Universitario de Ciencias de la Salud, Departamento de Microbiolog\u00eda y Patolog\u00eda, Instituto de Investigaci\u00f3n en C\u00e1ncer e Infecciones","place":["Guadalajara, Jalisco, Mexico"]},{"name":"Universidad de Guadalajara, Centro Universitario de Ciencias de la Salud, Departamento de Biolog\u00eda Molecular","place":["Guadalajara, Jalisco, Mexico"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mois\u00e9s","family":"Ramos-Solano","sequence":"additional","affiliation":[{"name":"Universidad de Guadalajara, Centro Universitario de Ciencias de la Salud, Departamento de Microbiolog\u00eda y Patolog\u00eda, Instituto de Investigaci\u00f3n en C\u00e1ncer e Infecciones","place":["Guadalajara, Jalisco, Mexico"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natali","family":"Vega-Maga\u00f1a","sequence":"additional","affiliation":[{"name":"Universidad de Guadalajara, Centro Universitario de Ciencias de la Salud, Departamento de Microbiolog\u00eda y Patolog\u00eda, Instituto de Investigaci\u00f3n en C\u00e1ncer e Infecciones","place":["Guadalajara, Jalisco, Mexico"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julio C\u00e9sar","family":"Villegas-Pineda","sequence":"additional","affiliation":[{"name":"Universidad de Guadalajara, Centro Universitario de Ciencias de la Salud, Departamento de Microbiolog\u00eda y Patolog\u00eda, Instituto de Investigaci\u00f3n en C\u00e1ncer e Infecciones","place":["Guadalajara, Jalisco, Mexico"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana Laura","family":"Pereira-Su\u00e1rez","sequence":"additional","affiliation":[{"name":"Universidad de Guadalajara, Centro Universitario de Ciencias de la Salud, Departamento de Microbiolog\u00eda y Patolog\u00eda, Instituto de Investigaci\u00f3n en C\u00e1ncer e Infecciones","place":["Guadalajara, Jalisco, Mexico"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,10,9]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.35369","article-title":"Global landscape of cervical cancer incidence and mortality in 2022 and predictions to 2030: The urgent need to address inequalities in cervical cancer","volume":"157","author":"Li","year":"2025","journal-title":"Int J Cancer"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jncc.2024.11.006","article-title":"Global burden of cervical cancer: Current estimates, temporal trend and future projections based on the GLOBOCAN 2022","volume":"5","author":"Wu","year":"2025","journal-title":"J Natl Cancer Center"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/j.critrevonc.2021.103343","article-title":"Dynamic crosstalk within the tumor microenvironment of uterine cervical carcinoma: Baseline network, iatrogenic alterations, and translational implications","volume":"162","author":"De Nola","year":"2021","journal-title":"Crit Rev Oncology\/Hematology"},{"key":"B4","doi-asserted-by":"publisher","first-page":"360","DOI":"10.1186\/s12916-020-01817-1","article-title":"Neutrophil to lymphocyte ratio and cancer prognosis: An umbrella review of systematic reviews and meta-analyses of observational studies","volume":"18","author":"Cupp","year":"2020","journal-title":"BMC Med"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/dju124","article-title":"Prognostic role of neutrophil-to-lymphocyte ratio in solid tumors: A systematic review and meta-analysis","volume":"106","author":"Templeton","year":"2014","journal-title":"JNCI: J Natl Cancer Institute"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.15157","article-title":"Prognostic significance of neutrophiltolymphocyte ratio in cervical cancer: A systematic review and metaanalysis of observational studies","volume":"8","author":"Huang","year":"2017","journal-title":"Oncotarget"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2024.1461175","article-title":"Evaluating the prognostic relevance of neutrophil-to-lymphocyte ratio in cervical cancer: A systematic review and meta-analysis","volume":"14","author":"Zhuang","year":"2024","journal-title":"Front Oncol"},{"key":"B8","doi-asserted-by":"publisher","first-page":"21917","DOI":"10.1038\/s41598-020-79071-x","article-title":"Neutrophil-to-lymphocyte ratio is an independent predictor for survival outcomes in cervical cancer: A systematic review and meta-analysis","volume":"10","author":"Zou","year":"2020","journal-title":"Sci Rep"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2025.1617662","article-title":"Cancer-associated fibroblast-mediated immune evasion: Molecular mechanisms of stromal-immune crosstalk in the tumor microenvironment","volume":"16","author":"Luo","year":"2025","journal-title":"Front Immunol"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.01835","article-title":"The dark side of fibroblasts: Cancer-associated fibroblasts as mediators of immunosuppression in the tumor microenvironment","volume":"10","author":"Monteran","year":"2019","journal-title":"Front Immunol"},{"key":"B11","doi-asserted-by":"publisher","first-page":"422","DOI":"10.1038\/s41419-018-0458-4","article-title":"Cancer-associated fibroblasts induce PDL1+ neutrophils through the IL6-STAT3 pathway that foster immune suppression in hepatocellular carcinoma","volume":"9","author":"Cheng","year":"2018","journal-title":"Cell Death Dis"},{"key":"B12","doi-asserted-by":"publisher","first-page":"96","DOI":"10.1007\/s00262-025-03946-z","article-title":"Cancer-associated fibroblasts promote pro-tumor functions of neutrophils in pancreatic cancer via IL-8: Potential suppression by pirfenidone","volume":"74","author":"Yagi","year":"2025","journal-title":"Cancer Immunol Immunother"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.01749","article-title":"The emerging role of neutrophil extracellular traps (NETs) in tumor progression and metastasis","volume":"11","author":"Masucci","year":"2020","journal-title":"Front Immunol"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1038\/s41568-025-00888-7","article-title":"Neutrophil extracellular traps in cancer","volume":"26","author":"Shahzad","year":"2026","journal-title":"Nat Rev Cancer"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2018-11-844548","article-title":"Neutrophil plasticity in the tumor microenvironment","volume":"133","author":"Giese","year":"2019","journal-title":"Blood"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1111\/imr.12459","article-title":"Neutrophils in the tumor microenvironment: Trying to heal the wound that cannot heal","volume":"273","author":"Singel","year":"2016","journal-title":"Immunol Rev"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.862257","article-title":"Editorial: Neutrophils in cancer","volume":"13","author":"Segal","year":"2022","journal-title":"Front Immunol"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2021.659445","article-title":"Stromal neutrophil extracellular trap density is an independent prognostic factor for cervical cancer recurrence","volume":"11","author":"Yan","year":"2021","journal-title":"Front Oncol"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.can-10-2583","article-title":"Tumor-associated neutrophils: New targets for cancer therapy","volume":"71","author":"Gregory","year":"2011","journal-title":"Cancer Res"},{"key":"B20","doi-asserted-by":"publisher","first-page":"590","DOI":"10.1002\/1878-0261.12630","article-title":"Cancer-associated V-ATPase induces delayed apoptosis of protumorigenic neutrophils","volume":"14","author":"Ibrahim","year":"2020","journal-title":"Mol Oncol"},{"key":"B21","doi-asserted-by":"publisher","first-page":"300","DOI":"10.1186\/rr73","article-title":"Collaborative interactions between neutrophil elastase and metalloproteinases in extracellular matrix degradation in three-dimensional collagen gels","volume":"2","author":"Zhu","year":"2001","journal-title":"Respir Res"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1002\/advs.202302613","article-title":"FGF19-induced inflammatory CAF promoted neutrophil extracellular trap formation in the liver metastasis of colorectal cancer","volume":"10","author":"Li","year":"2023","journal-title":"Adv Sci"},{"key":"B23","doi-asserted-by":"publisher","first-page":"683","DOI":"10.1038\/s41467-021-20982-2","article-title":"Stromal-driven and amyloid \u03b2-dependent induction of neutrophil extracellular traps modulates tumor growth","volume":"12","author":"Munir","year":"2021","journal-title":"Nat Commun"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2025.1537785","article-title":"Epithelial and macrophage cell interaction in cervical cancer through single-cell RNA-sequencing and spatial analysis","volume":"16","author":"Wang","year":"2025","journal-title":"Front Immunol"},{"key":"B25","doi-asserted-by":"publisher","first-page":"93","DOI":"10.1007\/s00432-023-05578-1","article-title":"Tumor-to-stroma cd8(+) t cells ratio combined with cancer-associated fibroblasts: An innovative approach to predicting lymph node metastases of cervical cancer","volume":"150","author":"Guo","year":"2024","journal-title":"J Cancer Res Clin Oncol"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2025.1612032","article-title":"T cell subsets in cervical cancer tumor microenvironment: Advances and therapeutic opportunities","volume":"16","author":"Guo","year":"2025","journal-title":"Front Immunol"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.3390\/cells10051073","article-title":"Myeloid-derived suppressor cells as therapeutic targets in uterine cervical and endometrial cancers","volume":"10","author":"Mabuchi","year":"2021","journal-title":"Cells"},{"key":"B28","doi-asserted-by":"publisher","first-page":"93","DOI":"10.3892\/or.2025.8926","article-title":"Crosstalk between cancer-associated fibroblasts and inflammation in tumor microenvironment: A novel perspective in cancer therapy (review)","volume":"54","author":"Liu","year":"2025","journal-title":"Oncol Rep"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.3390\/cancers17152484","article-title":"Cancer-associated fibroblasts: Immunosuppressive crosstalk with tumor-infiltrating immune cells and implications for therapeutic resistance","volume":"17","author":"Pawar","year":"2025","journal-title":"Cancers"},{"key":"B30","doi-asserted-by":"publisher","first-page":"1208","DOI":"10.1038\/s42003-022-04142-w","article-title":"Single-cell transcriptomics reveals cellular heterogeneity and molecular stratification of cervical cancer","volume":"5","author":"Li","year":"2022","journal-title":"Commun Biol"},{"key":"B31","doi-asserted-by":"publisher","first-page":"560","DOI":"10.3390\/cells13070560","article-title":"Phenotypic heterogeneity of cancer associated fibroblasts in cervical cancer progression: FAP as a central activation marker","volume":"13","author":"Bueno-Urquiza","year":"2024","journal-title":"Cells"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.3969\/j.issn.1007-3969.2014.04.003","article-title":"Cancer-associated fibroblasts promotes migration and invasion of cervical epithelial cancer cells through IL-6-induced \u201cepithelial-mesenchymal\u201d transition","volume":"24","author":"Chun-Xi","year":"2014","journal-title":"China Oncol"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.can-15-0732","article-title":"Stromal fibroblasts induce CCL20 through IL6\/C\/EBP\u03b2 to support the recruitment of Th17 cells during cervical cancer progression","volume":"75","author":"Walch-R\u00fcckheim","year":"2015","journal-title":"Cancer Res"},{"key":"B34","doi-asserted-by":"publisher","first-page":"S758","DOI":"10.1016\/j.annonc.2021.08.1232","article-title":"790p extracellular traps of the circulating neutrophils in CIN and cervical cancer","volume":"32","author":"Abakumova","year":"2021","journal-title":"Ann Oncol"},{"key":"B35","doi-asserted-by":"publisher","first-page":"1856","DOI":"10.3390\/cancers17111856","article-title":"The neutrophil-to-lymphocyte ratio (NLR) as a potential predictor in conization outcomes for cervical cancer","volume":"17","author":"Vida","year":"2025","journal-title":"Cancers (Basel)"},{"key":"B36","doi-asserted-by":"publisher","first-page":"039","DOI":"10.3889\/seejim.2025.6101","article-title":"Targeting STAT3 in neutrophils alters their immunoregulatory activity in cancer","volume":"8","author":"Jablonska","year":"2025","journal-title":"South East Eur J Immunol"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.01710","article-title":"Neutrophils as a therapeutic target in cancer","volume":"10","author":"Granot","year":"2019","journal-title":"Front Immunol"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.3390\/cancers18101509","article-title":"Differential protumoral mechanisms induced by CAFs in cervical cancer cells occur independently of 17\u03b2-estradiol stimulation","volume":"18","author":"Garc\u00eda-Bernal","year":"2026","journal-title":"Cancers"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcancer.2013.02.005","article-title":"Modulation of neutrophil granulocytes in the tumor microenvironment: Mechanisms and consequences for tumor progression","volume":"23","author":"Dumitru","year":"2013","journal-title":"Semin Cancer Biol"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1016\/j.ctarc.2025.101065","article-title":"Tumor-microbe transkingdom interactions in cancers at body interfaces: Mechanisms of neutrophil lifespan extension and functional reprogramming with therapeutic implications","volume":"46","author":"Mohamed","year":"2026","journal-title":"Cancer Treat Res Commun"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1016\/j.ceb.2025.102567","article-title":"Cancer-associated fibroblasts as mediators of tissue microenvironment remodeling in cancer","volume":"96","author":"Kugeratski","year":"2025","journal-title":"Curr Opin Cell Biol"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.00414","article-title":"Alteration of the antitumor immune response by cancer-associated fibroblasts","volume":"9","author":"Ziani","year":"2018","journal-title":"Front Immunol"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1016\/j.smim.2022.101595","article-title":"The role of neutrophil extracellular traps in cancer progression and metastasis","volume":"57","author":"De Meo","year":"2021","journal-title":"Semin Immunol"},{"key":"B44","doi-asserted-by":"publisher","first-page":"28","DOI":"10.20517\/cdr.2024.24","article-title":"Targeting NETosis: Nature's alarm system in cancer progression","volume":"7","author":"Yixia","year":"2024","journal-title":"Cancer Drug Resistance"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1155\/jimr\/5568021","article-title":"Neutrophil plasticity and NETosis in tumour microenvironment: Tumour evolution and therapy resistance","volume":"2026","author":"Soltani","year":"2026","journal-title":"J Immunol Res"},{"key":"B46","article-title":"Phenotype of circulating neutrophils at different stages of cervical neoplasia","volume":"21","author":"Abakumova","year":"2019","journal-title":"Med Immunol (Russia)"},{"key":"B47","doi-asserted-by":"publisher","first-page":"597","DOI":"10.1111\/cas.70294","article-title":"Single-cell and multiomic analysis reveals neutrophil heterogeneity and prognostic value in cervical lesions","volume":"117","author":"Wang","year":"2025","journal-title":"Cancer Sci"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2023.115622","article-title":"Microenvironmental regulation in tumor progression: Interactions between cancer-associated fibroblasts and immune cells","volume":"167","author":"Gao","year":"2023","journal-title":"Biomedicine Pharmacotherapy"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1900567\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T05:34:39Z","timestamp":1791524079000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1900567\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10,9]]},"references-count":48,"alternative-id":["10.3389\/fimmu.2026.1900567"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2026.1900567","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,10,9]]},"article-number":"1900567"}}