SYSTEMATIC REVIEW article
Front. Immunol.
Sec. Cancer Immunity and Immunotherapy
Volume 16 - 2025 | doi: 10.3389/fimmu.2025.1676854
This article is part of the Research TopicThe Role of Neutrophil Extra Cellular Traps (NETs) Formation in Tumor Microenvironment- from Basic Research to Clinical ApplicationsView all 7 articles
Neutrophil Extracellular Traps Predict Poor Survival in Cancer: A Systematic Review and Meta-Analysis of Studies on Tissue and Circulating Biomarkers
Provisionally accepted
- 1The Catholic University of Korea - Songsim Campus, Bucheon-si, Republic of Korea
- 2Department of Surgery, The Catholic University of Korea Seoul St Mary's Hospital, Seocho-gu, Republic of Korea
- 3Department of Hospital Pathology, The Catholic University of Korea Eunpyeong St Mary's Hospital, Eunpyeong-gu, Republic of Korea
- 4Department of Hospital Pathology,, The Catholic University of Korea Seoul St Mary's Hospital, Seocho-gu, Republic of Korea
Select one of your emails
You have multiple emails registered with Frontiers:
Notify me on publication
Please enter your email address:
If you already have an account, please login
You don't have a Frontiers account ? You can register here
ABSTRACT Background: Neutrophil extracellular traps (NETs) are fibrous, web like chromatin structures released by activated neutrophils that entrap and immobilize pathogens through histones, granule derived proteolytic enzymes, and myeloperoxidase (MPO) dependent mechanisms. Beyond host defense, NETs have been implicated in tumor progression; yet anticancer activity also has been reported, and findings vary across specimen types (tumor tissue versus blood) and detection methods, antibody panels, leaving their role in oncogenesis uncertain. We performed a systematic review and meta-analysis to define the prognostic significance of NETs in cancer, stratified by specimen type, detection technique, and antibody panels. Methods: Following PRISMA guidelines, we searched PubMed, EMBASE, and the Cochrane Library for studies published through August 10, 2023, that reported quantitative NET measurements linked to oncologic outcomes. Results: Fifteen studies (5,202 patients; publication years 2016–2023) reporting hazard ratios (HRs) for overall survival (OS) and disease free survival (DFS) relative to NET levels met inclusion criteria. Six studies evaluated tumor derived NETs in tissue and nine assessed circulating NETs in blood. Among tissue studies, two used immunohistochemistry for citrullinated histone H3 (H3Cit) alone, and four applied multiplex immunofluorescence for MPO/H3Cit or neutrophil elastase (NE)/H3Cit. Among blood studies, enzyme linked immunosorbent assays targeting MPO/DNA predominated, followed by H3Cit assays. Higher NET levels were significantly associated with worse OS (HR 1.80; 95% CI 1.35–2.41) and DFS (HR 2.26; 95% CI 1.82–2.82), irrespective of tissue or blood based measurement. Prognostic associations were robust for MPO/DNA, H3Cit, and NE, but not for cell free DNA.
Keywords: neutrophil extracellular traps, Neoplasms, prognosis, Systematic review as topic, Meta-Analysis as Topic
Received: 31 Jul 2025; Accepted: 22 Sep 2025.
Copyright: © 2025 Lee, Kim, Lee, Park and Yim. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Kwangil Yim, kangse_manse@catholic.ac.kr
Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.