Retrospective Study
Copyright ©The Author(s) 2025. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastrointest Oncol. Jul 15, 2025; 17(7): 105723
Published online Jul 15, 2025. doi: 10.4251/wjgo.v17.i7.105723
Neutrophil extracellular traps predict sensitivity to neoadjuvant chemotherapy combined with immunotherapy in locally advanced gastric cancer
Yuan Lv, Wei-Xuan Li, Liang Sun, Lin-Pu Xin, Tao Li, Wen-Tao Zhong, Hong-Yan Zhu, Ran An, Ai-Jun Liu, Lin Chen
Yuan Lv, Wei-Xuan Li, Lin Chen, Medical School of Chinese PLA, Beijing 100089, China
Yuan Lv, Liang Sun, Lin-Pu Xin, Tao Li, Wen-Tao Zhong, Department of General Surgery, The 7th Medical Center, Chinese PLA General Hospital, Beijing 100700, China
Yuan Lv, Tao Li, Medical Department of General Surgery, The 1st Medical Center, Chinese PLA General Hospital, Beijing 100089, China
Hong-Yan Zhu, Ran An, Ai-Jun Liu, Department of Pathology, The 7th Medical Center, Chinese PLA General Hospital, Beijing 100700, China
Co-first authors: Yuan Lv and Wei-Xuan Li.
Co-corresponding authors: Ai-Jun Liu and Lin Chen.
Author contributions: Chen L and Lv Y designed research; Lv Y, Li WX, Xin LP, Sun L, Li T, Zhong WT and Zhu HY performed research; Chen L and Liu AJ contributed new reagents or analytic tools; Lv Y, Li WX, Zhu HY, An R, and Liu AJ analyzed data; Lv Y and Li WX wrote the paper. All authors contributed to editorial changes in the manuscript, read and approved the final manuscript. Lv Y and Li WX contributed equally to this work as co-first authors. With the deepening of scientific research cooperation between Department of General Surgery and Department of Pathology, a single corresponding author can no longer meet the needs of all collaborators. Therefore, co-corresponding authors reflect equal contribution among the collaborating teams. Co-corresponding authors can enhance the academic recognition of a paper, especially since this research is an interdisciplinary research project where the two corresponding authors share different roles and responsibilities, such as fund application (Chen L) and data coordination (Liu AJ). The designation of two co-correspondences helps balance responsibility and contribution. Many high-quality journals (including WJGO) have two or more corresponding authors, which reflects the academic community's acceptance of co-corresponding authors.
Institutional review board statement: The study was reviewed and approved by the Medical Ethics Committee of Seventh Medical Center of Chinese PLA General Hospital (approval No. S2024-451-01).
Informed consent statement: Due to the anonymity and retrospective nature of the data, the written form of informed consent was waived.
Conflict-of-interest statement: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Data sharing statement: The datasets used and/or analyzed in the current study presented in the study are included in the article/ Supplementary information. Further inquiries can be directed to the corresponding author (Lin Chen, E-mail: Chenlinbj301@163.com) on reasonable request.
Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Lin Chen, MD, Assistant Professor, Medical School of Chinese PLA, No. 28 Fuxing Road, Haidian District, Beijing 100089, China. chenlinbj301@163.com
Received: February 5, 2025
Revised: May 1, 2025
Accepted: June 5, 2025
Published online: July 15, 2025
Processing time: 159 Days and 20.5 Hours
Abstract
BACKGROUND

Neutrophil extracellular traps (NETs) are associated with an immunosuppressive tumor microenvironment and may influence the efficacy of immune-based therapies. However, their role in neoadjuvant chemotherapy combined with immunotherapy (NACI) for locally advanced gastric cancer (LAGC) remains unclear.

AIM

To investigate the prognostic and predictive value of NET density in LAGC patients undergoing NACI.

METHODS

We enrolled 31 LAGC patients treated with NACI. NET density was assessed through dual immunofluorescence staining of citrullinated histone H3 and myeloperoxidase in pretreatment biopsy and post-treatment surgical specimens. Patients were stratified into high and low pre-NACI NET groups based on median NET density. Pathological complete response (pCR) and overall response rates were evaluated in relation to NET density. Logistic regression analyses were performed to identify independent predictors of treatment outcomes. Dynamic changes in NET density during NACI were also analyzed.

RESULTS

Patients with low pre-NACI NET density demonstrated significantly higher rates of pCR (40% vs 6%, P = 0.037) and overall response (53% vs 12%, P = 0.023) compared to those with high NET density. Low pre-NACI NET density and higher programmed death protein ligand 1 expression were identified as independent protective factors for achieving pCR and better response rates. NACI increased NET density; however, this increase was primarily observed in non-pCR and nonresponder groups. Patients in the pCR and responder groups showed stable NET density before and after treatment. Higher post-NACI NET density was associated with poorer respond to NACI. High post-NACI NET density was associated with increased infiltration of immunosuppressive FOXP3+ T regulatory cells (P = 0.025) and CD68+ macrophages (P = 0.038).

CONCLUSION

Pre-NACI NET density serves as a prognostic and predictive biomarker for NACI efficacy in LAGC patients. Low pretreatment NET density is associated with favorable outcomes, while increased post-treatment NET density correlates with poorer response. Targeting NET formation may represent a novel therapeutic strategy to enhance NACI efficacy in LAGC.

Keywords: Neutrophil extracellular traps; Locally advanced gastric cancer; Neoadjuvant chemotherapy; Neoadjuvant immunotherapy; Treatment sensitivity

Core Tip: This study identified neutrophil extracellular traps (NETs) as a novel prognostic and predictive biomarker for neoadjuvant chemotherapy combined with immunotherapy (NACI) in locally advanced gastric cancer (LAGC). Low pretreatment NET density correlated with higher pathological complete response and overall response rates, while increased post-treatment NET density was associated with poorer outcomes. These findings suggest that targeting NET formation could enhance NACI efficacy, offering a potential therapeutic strategy for LAGC patients.