Hypoxia-induced NETs establish a self-reinforcing immunosuppressive circuit that can be targeted to enhance immunotherapy in DLBCL
5 affiliations
- 1Department of Hematology, Northern Jiangsu Institute of Clinical Medicine, The Affiliated Huai’an No. 1 People’s Hospital of Nanjing Medical University, Huai’an City, Jiangsu Province 223300 China
- 2Key Laboratory of Autoimmune Disease of Huai’an Government; No. 1, West Huanghe Road, Huaiyin District, Huai’an City, Jiangsu Province 223300 China
- 3Department of Bioinformatics, School of Biomedical Engineering and Informatics, Nanjing Medical University, Nanjing City, Jiangsu Province 211166 China
- 4Collaborative Innovation Center for Personalized Cancer Medicine, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Nanjing Medical University, Nanjing City, Jiangsu Province 211166 China
- 5Department of Hematology; the Huai’an Clinical College of Xuzhou Medical University; No. 1, West Huanghe Road, Huaiyin District, Huai’an City, Jiangsu Province 223300 China
Abstract
Background: The efficacy of immune checkpoint inhibitors (ICI) in diffuse large B-cell lymphoma (DLBCL) is often limited by the immunosuppressive tumor microenvironment (TME), which comprises diverse cellular and non-cellular components. Among these, neutrophil extracellular traps (NETs) have emerged as potential immunomodulators that may contribute to immune suppression; however, their functional significance and regulatory mechanisms in DLBCL remain elusive.
Methods: NETs levels were evaluated in DLBCL patient specimens and their effects on clinical outcomes were analyzed. Using a syngeneic murine lymphoma model, we assessed the therapeutic effect of DNase I-mediated NET degradation, both alone and in combination with anti-PD-L1 antibody. Mechanistic investigations included in vivo macrophage depletion, transcriptomic profiling, and in vitro assays under normoxic and hypoxic conditions.
Results: NETs were significantly elevated in DLBCL tissues and were correlated with advanced disease stage, elevated PD-L1 expression, and poor survival. Deoxyribonuclease I (DNase I) treatment potently inhibited tumor growth and exhibited marked synergy with PD-L1 blockade. This combination therapy robustly reduced immunosuppressive macrophages and myeloid-derived suppressor cells while enhancing CD8+ T cell infiltration and function. Mechanistically, NETs promoted T cell exhaustion primarily through macrophage-dependent pathways and affected by the oxygen tension: under normoxia, NETs drove macrophages into a dysfunctional phenotype, whereas under hypoxia, they were associated with PI3K-Akt pathway to drive macrophages toward an immunosuppressive phenotype. Furthermore, hypoxia promoted NET formation via the HIF-1α/IL-8 axis, establishing a self-reinforcing immunosuppressive circuit.
Conclusion: Our study identifies NETs as pivotal regulators of immunosuppression in DLBCL and demonstrates that targeting NETs with DNase I effectively remodels the TME and enhances ICI efficacy, providing a compelling rationale for clinical translation of this combinatorial approach.
Graphical Abstract:
Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1186/s12967-026-08789-5.
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BibTeX
@article{lv2026hypoxiainduced,
title = {{Hypoxia-induced NETs establish a self-reinforcing immunosuppressive circuit that can be targeted to enhance immunotherapy in DLBCL}},
author = {Kebing Lv and Zhengmei He and Qiuni Chen and Yuye Shi and Lulu Wei and Yang Su and Dongnan Li and Shujun Tang and Kening Li and Chunling Wang and Liang Yu},
journal = {Journal of Translational Medicine},
year = {2026},
month = aug,
doi = {10.1186/s12967-026-08789-5},
url = {https://doi.org/10.1186/s12967-026-08789-5},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - Hypoxia-induced NETs establish a self-reinforcing immunosuppressive circuit that can be targeted to enhance immunotherapy in DLBCL
AU - Kebing Lv
AU - Zhengmei He
AU - Qiuni Chen
AU - Yuye Shi
AU - Lulu Wei
AU - Yang Su
AU - Dongnan Li
AU - Shujun Tang
AU - Kening Li
AU - Chunling Wang
AU - Liang Yu
PY - 2026
DA - 2026/08/19
JO - Journal of Translational Medicine
DO - 10.1186/s12967-026-08789-5
UR - https://doi.org/10.1186/s12967-026-08789-5
AB - Background: The efficacy of immune checkpoint inhibitors (ICI) in diffuse large B-cell lymphoma (DLBCL) is often limited by the immunosuppressive tumor microenvironment (TME), which comprises diverse cellular and non-cellular components. Among these, neutrophil extracellular traps (NETs) have emerged as potential immunomodulators that may contribute to immune suppression; however, their functional significance and regulatory mechanisms in DLBCL remain elusive. Methods: NETs levels were evaluated in DLBCL patient specimens and their effects on clinical outcomes were analyzed. Using a syngeneic murine lymphoma model, we assessed the therapeutic effect of DNase I-mediated NET degradation, both alone and in combination with anti-PD-L1 antibody. Mechanistic investigations included in vivo macrophage depletion, transcriptomic profiling, and in vitro assays under normoxic and hypoxic conditions. Results: NETs were significantly elevated in DLBCL tissues and were correlated with advanced disease stage, elevated PD-L1 expression, and poor survival. Deoxyribonuclease I (DNase I) treatment potently inhibited tumor growth and exhibited marked synergy with PD-L1 blockade. This combination therapy robustly reduced immunosuppressive macrophages and myeloid-derived suppressor cells while enhancing CD8+ T cell infiltration and function. Mechanistically, NETs promoted T cell exhaustion primarily through macrophage-dependent pathways and affected by the oxygen tension: under normoxia, NETs drove macrophages into a dysfunctional phenotype, whereas under hypoxia, they were associated with PI3K-Akt pathway to drive macrophages toward an immunosuppressive phenotype. Furthermore, hypoxia promoted NET formation via the HIF-1α/IL-8 axis, establishing a self-reinforcing immunosuppressive circuit. Conclusion: Our study identifies NETs as pivotal regulators of immunosuppression in DLBCL and demonstrates that targeting NETs with DNase I effectively remodels the TME and enhances ICI efficacy, providing a compelling rationale for clinical translation of this combinatorial approach. Graphical Abstract: Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1186/s12967-026-08789-5.
SN - 1479-5876
ER -