Henry Pham

Background: Although lung cancer’s prevalence has been declining over the years, it is still the leading cause of cancer related deaths.^1,2 The lungs being a common site of metastasis for many malignancies including osteosarcomas, renal cancers, and breast cancers could play a large part in this observation.³ Neutrophils and their production of neutrophil extracellular traps (NETs) has been attributed to play a role in lung cancer propagation and metastasis through their effects on the tumor microenvironment.^5,6,7,8,9,10 Currently, the pathway associated with NETs is a highly researched topic in hopes of understanding possible chemoimmunotherapy options that can reduce malignancies and prevent lung cancer related deaths.^4,6,7,8,9,10

Objective: In this narrative review, we explored two mechanisms in which NET imposes its effects on the tumor microenvironment, allowing for tumors to metastasize and evade host immunity.

Search Methods: An online search in the PubMed database was conducted from 2018 to 2025 using the following keywords: “Lung neoplasms”, “Neutrophil Extracellular Traps”, “Metastasis”, “Tumor Microenvironment”.

Results: Studies have shown NET to cause an epithelial to mesenchymal transition (EMT) through the downregulation of E-cadherin and upregulation of N-cadherin and vimentin.^3,5,6 These EMT changes has been attributed to the activation of the NLRP3 inflammasome pathway. NET activates the NLRP3 inflammasome pathway through the transcription factor NF-kB causing notable increase in both tumor size and tumor evasion capabilities.^6,7 MIR503HG is a long non-coding RNA that has been shown to directly downregulate NF-kB.⁶ However, other studies have shown that NET can also have an antagonistic effect on MIR503HG expression through a methylation process.⁸

NET has also been shown to cause CD8+ T cell exhaustion with the help of tumor associated macrophages (TAM).^7,10 Lung cancer cells upregulates CXCL5 on TAM through NF-kB. Neutrophils, when treated with CXCL5 from TAM showed increased NET formation.⁹ Cancer cells treated with these NETs then had higher exhaustion-associated genes with notable decline in CD8+ T cells and increase in pro-tumor M2 macrophages.^7,9  PD-L1, a known protein that prevents the immune system from attacking cancer cells, were found to be embedded in NETs.¹⁰ An anti PD-L1 therapy is currently the main chemoimmunotherapy available. It allows for recognition of cancer cells by T cells through the prevention of PD-L1 binding of PD-1 receptors.¹¹

Conclusion: Studies have found many pathways in which NET can impose its effects on the TME and allow for proliferation of cancer cells. Although there have been large breakthroughs upon the mechanism of NET, there is still much to be known. Understanding these mechanisms will allow for better targeted therapies for patients and possibly better outcomes.

Work Cited:

1. Kratzer TB, Bandi P, Freedman ND, et al. Lung cancer statistics, 2023. Cancer.2024;130(8):1330-1348. doi:10.1002/cncr.35128
2. Altorki NK, Markowitz GJ, Gao D, et al. The lung microenvironment: an important regulator of tumour growth and metastasis. Nat Rev Cancer. 2019;19(1):9-31. doi:10.1038/s41568-018-0081-9
3. Xiao G, Wang X, Xu Z, Liu Y, Jing J. Lung-specific metastasis: the coevolution of tumor cells and lung microenvironment. Mol Cancer. 2025;24(1):118. Published 2025 Apr 16.doi:10.1186/s12943-025-02318-6
4. Alexander M, Kim SY, Cheng H. Update 2020: Management of Non-Small Cell LungCancer. Lung. 2020;198(6):897-907. doi:10.1007/s00408-020-00407-5
5. Adrover JM, McDowell SAC, He XY, Quail DF, Egeblad M. NETworking with cancer: The bidirectional interplay between cancer and neutrophil extracellular traps. Cancer Cell.2023;41(3):505-526. doi:10.1016/j.ccell.2023.02.001
6. Wang Y, Liu F, Chen L, et al. Neutrophil Extracellular Traps (NETs) Promote Non-Small Cell Lung Cancer Metastasis by Suppressing lncRNA MIR503HG to Activate the NF-κB/NLRP3 Inflammasome Pathway. Front Immunol.2022;13:867516. Published 2022 May 30.doi:10.3389/fimmu.2022.867516
7. Li Y, Gong H, Chen X, et al. Synergistic effects of neutrophil extracellular traps and NF-κB on promoting tumor progression and immune evasion in lung adenocarcinoma. Int Immunopharmacol. 2026;169:116032. doi:10.1016/j.intimp.2025.116032
8. Ye X, Fang C, Hong W, et al. LncRNA MIR503HG regulates NETs-mediated NLRP3 inflammasome activation and NSCLC metastasis by enhancing the ubiquitination of C/EBPβ.Clin Transl Med. 2025;15(6):e70342. doi:10.1002/ctm2.70342
9. Lei Q, Zhen S, Zhang L, Zhao Q, Yang L, Zhang Y. A2AR-mediated CXCL5 upregulation on macrophages promotes NSCLC progression via NETosis. Cancer Immunol Immunother.2024;73(6):108. Published 2024 Apr 20. doi:10.1007/s00262-024-03689-3
10. Kaltenmeier C, Yazdani HO, Morder K, Geller DA, Simmons RL, Tohme S. NeutrophilExtracellular Traps Promote T Cell Exhaustion in the Tumor Microenvironment. Front Immunol.2021;12:785222. Published 2021 Nov 24. doi:10.3389/fimmu.2021.785222