{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,13]],"date-time":"2026-09-13T10:46:21Z","timestamp":1789296381028,"version":"build-2803163510"},"reference-count":122,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2026,3,8]],"date-time":"2026-03-08T00:00:00Z","timestamp":1772928000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004622","name":"Dutch Cancer Society","doi-asserted-by":"crossref","award":["15305"],"award-info":[{"award-number":["15305"]}],"id":[{"id":"10.13039\/501100004622","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Bennink Foundation and China Scholarship Council","award":["202307720025"],"award-info":[{"award-number":["202307720025"]}]},{"name":"Bennink Foundation and China Scholarship Council","award":["202407720066"],"award-info":[{"award-number":["202407720066"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Non-small cell lung cancer (NSCLC) remains a leading cause of cancer-related death. Although molecular stratification and multimodal therapy have improved outcomes in selected patients, overall prognosis is still limited by late diagnosis, heterogeneity, and treatment resistance. Immune checkpoint inhibitors (ICIs) have substantially improved survival outcomes in a subset of patients; however, the overall benefit remains limited, and both primary and acquired resistance are common. Neutrophils, as key effectors of innate immune responses, can be activated by diverse stimuli and release neutrophil extracellular traps (NETs). Growing evidence indicates that neutrophils and NETs contribute to remodeling of the tumor microenvironment (TME) in NSCLC, promoting resistance to ICIs. This review systematically summarizes the biological features, key molecular pathways, and inducing factors of neutrophils and NETs in lung cancer and synthesizes evidence supporting their roles as biomarkers of ICI efficacy and prognosis. We further focus on the mechanisms by which NETs mediate immunosuppression and foster an immune-excluded TME, thereby driving resistance to immunotherapy. In addition, we outline potential therapeutic and combination strategies targeting neutrophils and NETs, providing a theoretical basis for developing optimized immunotherapy approaches for NSCLC that target neutrophils and NETs.<\/jats:p>","DOI":"10.3390\/biom16030400","type":"journal-article","created":{"date-parts":[[2026,3,9]],"date-time":"2026-03-09T11:06:52Z","timestamp":1773054412000},"page":"400","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["The Neutrophil\u2013NET Axis in Immune Checkpoint Inhibitor Resistance in Non-Small Cell Lung Cancer: Roles, Biomarkers and Therapeutic Opportunities"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4597-8729","authenticated-orcid":false,"given":"Geng","family":"Xu","sequence":"first","affiliation":[{"name":"Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, Vrije Universiteit, 1081 HV Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-8086-7110","authenticated-orcid":false,"given":"Bing","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, Vrije Universiteit, 1081 HV Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7565-7504","authenticated-orcid":false,"given":"Elisa","family":"Giovannetti","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, Vrije Universiteit, 1081 HV Amsterdam, The Netherlands"},{"name":"Cancer Pharmacology Laboratory, Fondazione Pisana per la Scienza, Via Ferruccio Giovannini 13, 56017 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,8]]},"reference":[{"key":"ref_1","first-page":"229","article-title":"Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"74","author":"Bray","year":"2024","journal-title":"CA Cancer J. Clin."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"288","DOI":"10.21037\/tlcr.2016.06.07","article-title":"Non-small cell lung cancer: Current treatment and future advances","volume":"5","author":"Zappa","year":"2016","journal-title":"Transl. Lung Cancer Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"249","DOI":"10.6004\/jnccn.2204.0023","article-title":"Non-Small Cell Lung Cancer, Version 4.2024, NCCN Clinical Practice Guidelines in Oncology","volume":"22","author":"Riely","year":"2024","journal-title":"J. Natl. Compr. Cancer Netw."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"iii27","DOI":"10.1093\/annonc\/mdu199","article-title":"Metastatic non-small-cell lung cancer (NSCLC): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up","volume":"25","author":"Reck","year":"2014","journal-title":"Ann. Oncol. Off. J. Eur. Soc. Med. Oncol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1992","DOI":"10.1200\/JCO.22.01989","article-title":"Pembrolizumab Plus Pemetrexed and Platinum in Nonsquamous Non-Small-Cell Lung Cancer: 5-Year Outcomes from the Phase 3 KEYNOTE-189 Study","volume":"41","author":"Garassino","year":"2023","journal-title":"J. Clin. Oncol."},{"key":"ref_6","first-page":"e98184","article-title":"Efficacy and Pulmonary Outcomes of Dual Immunotherapy Plus Chemotherapy Versus Standard Chemotherapy in Advanced Non-small Cell Lung Cancer","volume":"17","year":"2025","journal-title":"Cureus"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"5154","DOI":"10.1038\/s41467-023-40745-5","article-title":"Acquired resistance to anti-PD1 therapy in patients with NSCLC associates with immunosuppressive T cell phenotype","volume":"14","author":"Hiltbrunner","year":"2023","journal-title":"Nat. Commun."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"520","DOI":"10.1016\/j.tips.2024.04.006","article-title":"Immune checkpoint blockade resistance in lung cancer: Emerging mechanisms and therapeutic opportunities","volume":"45","author":"Konen","year":"2024","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1038\/s41392-024-01979-x","article-title":"Cold and hot tumors: From molecular mechanisms to targeted therapy","volume":"9","author":"Wu","year":"2024","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_10","first-page":"21","article-title":"Tumor microenvironment-driven resistance to immunotherapy in non-small cell lung cancer: Strategies for Cold-to-Hot tumor transformation","volume":"8","author":"Yu","year":"2025","journal-title":"Cancer Drug Resist."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1038\/nrc.2016.52","article-title":"Neutrophils in cancer: Neutral no more","volume":"16","author":"Coffelt","year":"2016","journal-title":"Nat. Rev. Cancer"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"e27","DOI":"10.4110\/in.2018.18.e27","article-title":"Damage-Associated Molecular Patterns in Inflammatory Diseases","volume":"18","author":"Roh","year":"2018","journal-title":"Immune Netw."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1038\/s41392-023-01452-1","article-title":"Macrophages in immunoregulation and therapeutics","volume":"8","author":"Chen","year":"2023","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Poto, R., Cristinziano, L., Modestino, L., de Paulis, A., Marone, G., Loffredo, S., Galdiero, M.R., and Varricchi, G. (2022). Neutrophil Extracellular Traps, Angiogenesis and Cancer. Biomedicines, 10.","DOI":"10.3390\/biomedicines10020431"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1016\/j.ccell.2023.02.001","article-title":"NETworking with cancer: The bidirectional interplay between cancer and neutrophil extracellular traps","volume":"41","author":"Adrover","year":"2023","journal-title":"Cancer Cell"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Horaguchi, S., Nakahara, Y., Igarashi, Y., Kouro, T., Wei, F., Murotani, K., Udagawa, S., Higashijima, N., Matsuo, N., and Murakami, S. (2024). Prognostic Significance of Plasma Neutrophil Extracellular Trap Levels in Patients with Non-Small Cell Lung Cancer Treated with Immune Checkpoint Inhibitors. Biomedicines, 12.","DOI":"10.3390\/biomedicines12081831"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Chen, Q., Zhang, L., Li, X., and Zhuo, W. (2021). Neutrophil Extracellular Traps in Tumor Metastasis: Pathological Functions and Clinical Applications. Cancers, 13.","DOI":"10.3390\/cancers13112832"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1038\/s41568-025-00888-7","article-title":"Neutrophil extracellular traps in cancer","volume":"26","author":"Shahzad","year":"2025","journal-title":"Nat. Rev. Cancer"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Rosales, C. (2018). Neutrophil: A Cell with Many Roles in Inflammation or Several Cell Types?. Front. Physiol., 9.","DOI":"10.3389\/fphys.2018.00113"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1038\/nri3399","article-title":"Neutrophil recruitment and function in health and inflammation","volume":"13","author":"Kolaczkowska","year":"2013","journal-title":"Nat. Rev. Immunol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"657","DOI":"10.1016\/j.immuni.2010.11.011","article-title":"Neutrophils, from marrow to microbes","volume":"33","author":"Borregaard","year":"2010","journal-title":"Immunity"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Stankovic, B., Bj\u00f8rhovde, H.A.K., Skarshaug, R., Aamodt, H., Frafjord, A., M\u00fcller, E., Hammarstr\u00f6m, C., Beraki, K., B\u00e6kkevold, E.S., and Woldb\u00e6k, P.R. (2018). Immune Cell Composition in Human Non-small Cell Lung Cancer. Front. Immunol., 9.","DOI":"10.3389\/fimmu.2018.03101"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"14381","DOI":"10.1038\/ncomms14381","article-title":"Neutrophils dominate the immune cell composition in non-small cell lung cancer","volume":"8","author":"Kargl","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"601","DOI":"10.1038\/s41571-019-0222-4","article-title":"Tumour-associated neutrophils in patients with cancer","volume":"16","author":"Shaul","year":"2019","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"943","DOI":"10.1016\/j.jtho.2017.03.010","article-title":"Lung Adenocarcinoma and Squamous Cell Carcinoma Gene Expression Subtypes Demonstrate Significant Differences in Tumor Immune Landscape","volume":"12","author":"Faruki","year":"2017","journal-title":"J. Thorac. Oncol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"562","DOI":"10.1016\/j.celrep.2014.12.039","article-title":"Phenotypic diversity and plasticity in circulating neutrophil subpopulations in cancer","volume":"10","author":"Sagiv","year":"2015","journal-title":"Cell Rep."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"e202302332","DOI":"10.26508\/lsa.202302332","article-title":"Immunosuppressive low-density neutrophils in the blood of cancer patients display a mature phenotype","volume":"7","author":"Vanhaver","year":"2024","journal-title":"Life Sci. Alliance"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Valadez-Cosmes, P., Maitz, K., Kindler, O., Raftopoulou, S., Kienzl, M., Santiso, A., Mihalic, Z.N., Brcic, L., Lindenmann, J., and Fediuk, M. (2021). Identification of Novel Low-Density Neutrophil Markers Through Unbiased High-Dimensional Flow Cytometry Screening in Non-Small Cell Lung Cancer Patients. Front. Immunol., 12.","DOI":"10.3389\/fimmu.2021.703846"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1016\/j.ccr.2009.06.017","article-title":"Polarization of Tumor-Associated Neutrophil Phenotype by TGF-\u03b2: \u201cN1\u201d versus \u201cN2\u201d TAN","volume":"16","author":"Fridlender","year":"2009","journal-title":"Cancer Cell"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1016\/j.critrevonc.2011.06.004","article-title":"On the dual roles and polarized phenotypes of neutrophils in tumor development and progression","volume":"82","author":"Piccard","year":"2012","journal-title":"Crit. Rev. Oncol. Hematol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1158\/2326-6066.CIR-16-0297","article-title":"Myeloid-Derived Suppressor Cells","volume":"5","author":"Gabrilovich","year":"2017","journal-title":"Cancer Immunol. Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"822","DOI":"10.1158\/2159-8290.CD-18-0099","article-title":"STK11\/LKB1 Mutations and PD-1 Inhibitor Resistance in KRAS-Mutant Lung Adenocarcinoma","volume":"8","author":"Skoulidis","year":"2018","journal-title":"Cancer Discov."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1016\/j.jtho.2021.10.013","article-title":"Diminished Efficacy of Programmed Death-(Ligand)1 Inhibition in STK11- and KEAP1-Mutant Lung Adenocarcinoma Is Affected by KRAS Mutation Status","volume":"17","author":"Ricciuti","year":"2022","journal-title":"J. Thorac. Oncol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"999","DOI":"10.1158\/0008-5472.CAN-15-1439","article-title":"STK11\/LKB1 Deficiency Promotes Neutrophil Recruitment and Proinflammatory Cytokine Production to Suppress T-cell Activity in the Lung Tumor Microenvironment","volume":"76","author":"Koyama","year":"2016","journal-title":"Cancer Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"113295","DOI":"10.1016\/j.celrep.2023.113295","article-title":"KEAP1 mutation in lung adenocarcinoma promotes immune evasion and immunotherapy resistance","volume":"42","author":"Zavitsanou","year":"2023","journal-title":"Cell Rep."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"e000706","DOI":"10.1136\/esmoopen-2020-000706","article-title":"STK11 and KEAP1 mutations as prognostic biomarkers in an observational real-world lung adenocarcinoma cohort","volume":"5","author":"Doshi","year":"2020","journal-title":"ESMO Open"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"462","DOI":"10.1038\/s41586-024-07943-7","article-title":"CTLA4 blockade abrogates KEAP1\/STK11-related resistance to PD-(L)1 inhibitors","volume":"635","author":"Skoulidis","year":"2024","journal-title":"Nature"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1186\/s12929-022-00879-y","article-title":"Spatial multi-omics analyses of the tumor immune microenvironment","volume":"29","author":"Hsieh","year":"2022","journal-title":"J. Biomed. Sci."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Kumar, G., Pandurengan, R.K., Parra, E.R., Kannan, K., and Haymaker, C. (2023). Spatial modelling of the tumor microenvironment from multiplex immunofluorescence images: Methods and applications. Front. Immunol., 14.","DOI":"10.3389\/fimmu.2023.1288802"},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Kang, D.H., Kim, Y., Lee, J.H., Kang, H.S., and Chung, C. (2025). Spatial Transcriptomics in Lung Cancer and Pulmonary Diseases: A Comprehensive Review. Cancers, 17.","DOI":"10.3390\/cancers17121912"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"e22946","DOI":"10.4161\/onci.22946","article-title":"Neutrophil extracellular traps: A new link to cancer-associated thrombosis and potential implications for tumor progression","volume":"2","author":"Demers","year":"2013","journal-title":"Oncoimmunology"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"633","DOI":"10.1016\/j.trecan.2016.10.012","article-title":"Immunity Gone Astray\u2014NETs in Cancer","volume":"2","author":"Cedervall","year":"2016","journal-title":"Trends Cancer"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1038\/s41392-024-01933-x","article-title":"Neutrophil extracellular traps in homeostasis and disease","volume":"9","author":"Wang","year":"2024","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"797","DOI":"10.1002\/JLB.3RU0620-375R","article-title":"The vitals of NETs","volume":"110","author":"Tan","year":"2021","journal-title":"J. Leukoc. Biol."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Konig, M.F., and Andrade, F. (2016). A Critical Reappraisal of Neutrophil Extracellular Traps and NETosis Mimics Based on Differential Requirements for Protein Citrullination. Front. Immunol., 7.","DOI":"10.3389\/fimmu.2016.00461"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"100116","DOI":"10.1016\/j.rpth.2023.100116","article-title":"Novel mechanisms of thrombo-inflammation during infection: Spotlight on neutrophil extracellular trap-mediated platelet activation","volume":"7","author":"Colicchia","year":"2023","journal-title":"Res. Pract. Thromb. Haemost."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1607","DOI":"10.1111\/jth.15313","article-title":"PAD4 takes charge during neutrophil activation: Impact of PAD4 mediated NET formation on immune-mediated disease","volume":"19","author":"Liu","year":"2021","journal-title":"J. Thromb. Haemost."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1146\/annurev-cellbio-020520-111016","article-title":"Cellular Mechanisms of NETosis","volume":"36","author":"Thiam","year":"2020","journal-title":"Annu. Rev. Cell Dev. Biol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"2319","DOI":"10.1182\/bloodadvances.2020003377","article-title":"Neutrophil extracellular traps and inflammasomes cooperatively promote venous thrombosis in mice","volume":"5","author":"Campos","year":"2021","journal-title":"Blood Adv."},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Li, Y., Zhang, Z., Hu, Y., Yan, X., Song, Q., Wang, G., Chen, R., Jiao, S., and Wang, J. (2020). Pretreatment Neutrophil-to-Lymphocyte Ratio (NLR) May Predict the Outcomes of Advanced Non-small-cell Lung Cancer (NSCLC) Patients Treated with Immune Checkpoint Inhibitors (ICIs). Front. Oncol., 10.","DOI":"10.3389\/fonc.2020.00654"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"106677","DOI":"10.1016\/j.intimp.2020.106677","article-title":"Predictive value of neutrophil-lymphocyte ratio and platelet-lymphocyte ratio in non-small cell lung cancer patients treated with immune checkpoint inhibitors: A meta-analysis","volume":"85","author":"Zhang","year":"2020","journal-title":"Int. Immunopharmacol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.lungcan.2017.01.013","article-title":"Pretreatment neutrophil-to-lymphocyte ratio as a marker of outcomes in nivolumab-treated patients with advanced non-small-cell lung cancer","volume":"106","author":"Bagley","year":"2017","journal-title":"Lung Cancer"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"955","DOI":"10.2147\/OTT.S153290","article-title":"Prognostic utility of baseline neutrophil-to-lymphocyte ratio in patients receiving immune checkpoint inhibitors: A review and meta-analysis","volume":"11","author":"Sacdalan","year":"2018","journal-title":"OncoTargets Ther."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"e049123","DOI":"10.1136\/bmjopen-2021-049123","article-title":"Prognostic value of derived neutrophil-to-lymphocyte ratio (dNLR) in patients with non-small cell lung cancer receiving immune checkpoint inhibitors: A meta-analysis","volume":"11","author":"Yang","year":"2021","journal-title":"BMJ Open"},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Arasanz, H., Bocanegra, A.I., Morilla, I., Fern\u00e1ndez-Irigoyen, J., Mart\u00ednez-Aguillo, M., Teijeira, L., Garnica, M., Blanco, E., Chocarro, L., and Ausin, K. (2022). Circulating Low Density Neutrophils Are Associated with Resistance to First Line Anti-PD1\/PDL1 Immunotherapy in Non-Small Cell Lung Cancer. Cancers, 14.","DOI":"10.1101\/2022.04.27.22273598"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1212","DOI":"10.21037\/tlcr-24-808","article-title":"Comparing neutrophil-to-lymphocyte ratio (NLR), absolute neutrophil count (ANC) and derived NLR as predictive biomarkers in first-line immunotherapy for non-small cell lung cancer: A retrospective study","volume":"14","author":"Longueville","year":"2025","journal-title":"Transl. Lung Cancer Res."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"426","DOI":"10.1016\/j.cllc.2018.04.008","article-title":"Correlation of Neutrophil to Lymphocyte Ratio and Absolute Neutrophil Count With Outcomes With PD-1 Axis Inhibitors in Patients With Advanced Non-Small-Cell Lung Cancer","volume":"19","author":"Zer","year":"2018","journal-title":"Clin. Lung Cancer"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1164\/rccm.201808-1502LE","article-title":"The Ratio of Peripheral Regulatory T Cells to Lox-1(+) Polymorphonuclear Myeloid-derived Suppressor Cells Predicts the Early Response to Anti-PD-1 Therapy in Patients with Non-Small Cell Lung Cancer","volume":"199","author":"Kim","year":"2019","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"9050","DOI":"10.1038\/s41598-020-65666-x","article-title":"Peripheral natural killer cells and myeloid-derived suppressor cells correlate with anti-PD-1 responses in non-small cell lung cancer","volume":"10","author":"Youn","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1016\/j.ejca.2021.03.011","article-title":"Predicting immunotherapy outcomes under therapy in patients with advanced NSCLC using dNLR and its early dynamics","volume":"151","author":"Mezquita","year":"2021","journal-title":"Eur. J. Cancer"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"S272","DOI":"10.1016\/j.jtho.2019.08.547","article-title":"Circulating Immature Neutrophils, Tumor-Associated Neutrophils and dNLR for Identification of Fast Progressors to Immunotherapy in NSCLC","volume":"14","author":"Mezquita","year":"2019","journal-title":"J. Thorac. Oncol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"3403","DOI":"10.1111\/febs.17144","article-title":"A combined model of serum neutrophil extracellular traps, CD8(+) T cells, and tumor proportion score provides better prediction of PD-1 inhibitor efficacy in patients with NSCLC","volume":"291","author":"Guo","year":"2024","journal-title":"FEBS J."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"17588359251387551","DOI":"10.1177\/17588359251387551","article-title":"Neutrophil extracellular traps predict poor response and prognosis in non-small cell lung cancer immunotherapy","volume":"17","author":"Lv","year":"2025","journal-title":"Ther. Adv. Med. Oncol."},{"key":"ref_64","doi-asserted-by":"crossref","unstructured":"Hong, W., Ye, X., Chen, L., Chai, X., Yin, Y., Li, Z., Fang, C., Qian, X., Yu, B., and Qin, G. (2026). Prognostic value of tumour-associated neutrophils in different polarization status releasing neutrophil extracellular traps in the immunotherapy of advanced non-small cell lung cancer. Front. Oncol., 15.","DOI":"10.3389\/fonc.2025.1705716"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"17864","DOI":"10.18632\/aging.203289","article-title":"A innovative prognostic symbol based on neutrophil extracellular traps (NETs)-related lncRNA signature in non-small-cell lung cancer","volume":"13","author":"Fang","year":"2021","journal-title":"Aging"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"3407","DOI":"10.21037\/tlcr-24-463","article-title":"Construction of a neutrophil extracellular trap formation-related gene model for predicting the survival of lung adenocarcinoma patients and their response to immunotherapy","volume":"13","author":"Wang","year":"2024","journal-title":"Transl. Lung Cancer Res."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"18226","DOI":"10.1038\/s41598-023-45289-8","article-title":"Construction and validation of a novel prognostic model of neutrophil-related genes signature of lung adenocarcinoma","volume":"13","author":"Zhu","year":"2023","journal-title":"Sci. Rep."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"773","DOI":"10.1038\/s41587-019-0114-2","article-title":"Determining cell type abundance and expression from bulk tissues with digital cytometry","volume":"37","author":"Newman","year":"2019","journal-title":"Nat. Biotechnol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"W509","DOI":"10.1093\/nar\/gkaa407","article-title":"TIMER2.0 for analysis of tumor-infiltrating immune cells","volume":"48","author":"Li","year":"2020","journal-title":"Nucleic Acids Res."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1038\/s41577-020-00490-y","article-title":"Myeloid-derived suppressor cells in the era of increasing myeloid cell diversity","volume":"21","author":"Veglia","year":"2021","journal-title":"Nat. Rev. Immunol."},{"key":"ref_71","first-page":"10732748241285474","article-title":"Predictability of Neutrophile to Lymphocyte Ratio and Platelet to Lymphocyte Ratio on the Effectiveness of Immune Checkpoint Inhibitors in Non-small Cell Lung Cancer patients: A Meta-Analysis","volume":"31","author":"Nguyen","year":"2024","journal-title":"Cancer Control J. Moffitt Cancer Cent."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"1079","DOI":"10.2147\/JIR.S347777","article-title":"Tumor-Infiltrating PD-L1+ Neutrophils Induced by GM-CSF Suppress T Cell Function in Laryngeal Squamous Cell Carcinoma and Predict Unfavorable Prognosis","volume":"15","author":"Tang","year":"2022","journal-title":"J. Inflamm. Res."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"100825","DOI":"10.1016\/j.tranon.2020.100825","article-title":"Tumor-associated neutrophils suppress antitumor immunity of NK cells through the PD-L1\/PD-1 axis","volume":"13","author":"Sun","year":"2020","journal-title":"Transl. Oncol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1186\/s40425-017-0308-4","article-title":"Inhibition of arginase by CB-1158 blocks myeloid cell-mediated immune suppression in the tumor microenvironment","volume":"5","author":"Steggerda","year":"2017","journal-title":"J. Immunother. Cancer"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1016\/j.ccell.2023.03.004","article-title":"Neutralizing IL-8 potentiates immune checkpoint blockade efficacy for glioma","volume":"41","author":"Liu","year":"2023","journal-title":"Cancer Cell"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"2188","DOI":"10.1016\/j.immuni.2023.09.011","article-title":"The cancer-immunity cycle: Indication, genotype, and immunotype","volume":"56","author":"Mellman","year":"2023","journal-title":"Immunity"},{"key":"ref_77","doi-asserted-by":"crossref","unstructured":"Tiwari, A., Oravecz, T., Dillon, L.A., Italiano, A., Audoly, L., Fridman, W.H., and Clifton, G.T. (2023). Towards a consensus definition of immune exclusion in cancer. Front. Immunol., 14.","DOI":"10.3389\/fimmu.2023.1084887"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"2606","DOI":"10.1158\/2159-8290.CD-21-1714","article-title":"Spatial Positioning and Matrix Programs of Cancer-Associated Fibroblasts Promote T-cell Exclusion in Human Lung Tumors","volume":"12","author":"Grout","year":"2022","journal-title":"Cancer Discov."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"1353","DOI":"10.1038\/s41416-020-1020-6","article-title":"T-cell tumour exclusion and immunotherapy resistance: A role for CAF targeting","volume":"123","author":"Hanley","year":"2020","journal-title":"Br. J. Cancer"},{"key":"ref_80","doi-asserted-by":"crossref","unstructured":"Koppensteiner, L., Mathieson, L., O\u2019Connor, R.A., and Akram, A.R. (2022). Cancer Associated Fibroblasts\u2014An Impediment to Effective Anti-Cancer T Cell Immunity. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.887380"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"396","DOI":"10.1016\/j.ccell.2023.12.021","article-title":"Cancer-associated fibroblast phenotypes are associated with patient outcome in non-small cell lung cancer","volume":"42","author":"Cords","year":"2024","journal-title":"Cancer Cell"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"856","DOI":"10.1016\/j.immuni.2020.03.001","article-title":"CXCR1 and CXCR2 Chemokine Receptor Agonists Produced by Tumors Induce Neutrophil Extracellular Traps that Interfere with Immune Cytotoxicity","volume":"52","author":"Teijeira","year":"2020","journal-title":"Immunity"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"729","DOI":"10.1016\/j.immuni.2020.04.009","article-title":"Neutrophils Create an ImpeNETrable Shield between Tumor and Cytotoxic Immune Cells","volume":"52","author":"Ireland","year":"2020","journal-title":"Immunity"},{"key":"ref_84","doi-asserted-by":"crossref","unstructured":"Fang, Q., Stehr, A.M., Naschberger, E., Knopf, J., Herrmann, M., and St\u00fcrzl, M. (2022). No NETs no TIME: Crosstalk between neutrophil extracellular traps and the tumor immune microenvironment. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.1075260"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1016\/j.bbrc.2022.06.052","article-title":"Exenatide enhanced the antitumor efficacy on PD-1 blockade by the attenuation of neutrophil extracellular traps","volume":"619","author":"Chen","year":"2022","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"3561","DOI":"10.1158\/0008-5472.CAN-21-4045","article-title":"A Novel Selective Inhibitor JBI-589 Targets PAD4-Mediated Neutrophil Migration to Suppress Tumor Progression","volume":"82","author":"Deng","year":"2022","journal-title":"Cancer Res."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"104254","DOI":"10.1016\/j.cellimm.2020.104254","article-title":"IL-6 as a major regulator of MDSC activity and possible target for cancer immunotherapy","volume":"359","author":"Weber","year":"2021","journal-title":"Cell. Immunol."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"e010612","DOI":"10.1136\/jitc-2024-010612","article-title":"Cell-intrinsic PD-L1 signaling drives immunosuppression by myeloid-derived suppressor cells through IL-6\/Jak\/Stat3 in PD-L1-high lung cancer","volume":"13","author":"Jeong","year":"2025","journal-title":"J. Immunother. Cancer"},{"key":"ref_89","doi-asserted-by":"crossref","unstructured":"Kelley, N., Jeltema, D., Duan, Y., and He, Y. (2019). The NLRP3 Inflammasome: An Overview of Mechanisms of Activation and Regulation. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20133328"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"1141","DOI":"10.1038\/s41423-021-00670-3","article-title":"An update on the regulatory mechanisms of NLRP3 inflammasome activation","volume":"18","author":"Paik","year":"2021","journal-title":"Cell. Mol. Immunol."},{"key":"ref_91","doi-asserted-by":"crossref","unstructured":"Gritsenko, A., Yu, S., Martin-Sanchez, F., Diaz-del-Olmo, I., Nichols, E.-M., Davis, D.M., Brough, D., and Lopez-Castejon, G. (2020). Priming Is Dispensable for NLRP3 Inflammasome Activation in Human Monocytes In Vitro. Front. Immunol., 11.","DOI":"10.3389\/fimmu.2020.565924"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"2517","DOI":"10.1038\/s41388-024-03100-6","article-title":"PIM1\/NF-\u03baB\/CCL2 blockade enhances anti-PD-1 therapy response by modulating macrophage infiltration and polarization in tumor microenvironment of NSCLC","volume":"43","author":"Chen","year":"2024","journal-title":"Oncogene"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1038\/s41423-023-00974-6","article-title":"The chemokines CXCL8 and CXCL12: Molecular and functional properties, role in disease and efforts towards pharmacological intervention","volume":"20","author":"Cambier","year":"2023","journal-title":"Cell. Mol. Immunol."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"101516","DOI":"10.1016\/j.smim.2021.101516","article-title":"G-CSF\u2014A double edge sword in neutrophil mediated immunity","volume":"54","author":"Martin","year":"2021","journal-title":"Semin. Immunol."},{"key":"ref_95","doi-asserted-by":"crossref","unstructured":"Raftopoulou, S., Valadez-Cosmes, P., Mihalic, Z.N., Schicho, R., and Kargl, J. (2022). Tumor-Mediated Neutrophil Polarization and Therapeutic Implications. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23063218"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"e000326","DOI":"10.1136\/jitc-2019-000326","article-title":"Simultaneous inhibition of CXCR1\/2, TGF-\u03b2, and PD-L1 remodels the tumor and its microenvironment to drive antitumor immunity","volume":"8","author":"Horn","year":"2020","journal-title":"J. Immunother. Cancer"},{"key":"ref_97","unstructured":"(2026, February 01). ClinicalTrials.gov. SX-682 With Pembrolizumab for the Treatment of Metastatic or Recurrent Stage IIIC or IV Non-Small Cell Lung Cancer. Identifier: NCT05570825, Available online: https:\/\/clinicaltrials.gov\/study\/NCT05570825."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1016\/j.lungcan.2022.06.010","article-title":"STK11 and KEAP1 mutations in non-small cell lung cancer patients: Descriptive analysis and prognostic value among Hispanics (STRIKE registry-CLICaP)","volume":"170","author":"Corassa","year":"2022","journal-title":"Lung Cancer"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"116334","DOI":"10.1016\/j.biopha.2024.116334","article-title":"Targeting neutrophil extracellular traps: A novel strategy in hematologic malignancies","volume":"173","author":"Liu","year":"2024","journal-title":"Biomed. Pharmacother."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"e12808","DOI":"10.1002\/rth2.12808","article-title":"Building a better NET: Neutrophil extracellular trap targeted therapeutics in the treatment of infectious and inflammatory disorders","volume":"6","author":"Ngo","year":"2022","journal-title":"Res. Pract. Thromb. Haemost."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1016\/j.jcf.2019.08.020","article-title":"Single dose escalation studies with inhaled POL6014, a potent novel selective reversible inhibitor of human neutrophil elastase, in healthy volunteers and subjects with cystic fibrosis","volume":"19","author":"Barth","year":"2020","journal-title":"J. Cyst. Fibros. Off. J. Eur. Cyst. Fibros. Soc."},{"key":"ref_102","doi-asserted-by":"crossref","unstructured":"Ruffini, P.A. (2019). The CXCL8-CXCR1\/2 Axis as a Therapeutic Target in Breast Cancer Stem-Like Cells. Front. Oncol., 9.","DOI":"10.3389\/fonc.2019.00040"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1186\/s13045-021-01053-x","article-title":"Novel therapies emerging in oncology to target the TGF-\u03b2 pathway","volume":"14","author":"Kim","year":"2021","journal-title":"J. Hematol. Oncol."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"9508","DOI":"10.1200\/JCO.2024.42.16_suppl.9508","article-title":"Safety and efficacy of first-in-class CXCR1\/2 inhibitor SX-682 in combination with pembrolizumab (pem) in patients (pts) with metastatic melanoma (mMEL) with disease progression on anti\u2013PD-1 therapy","volume":"42","author":"Patel","year":"2024","journal-title":"J. Clin. Oncol."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1007\/s10637-023-01410-2","article-title":"CXCR2 antagonist navarixin in combination with pembrolizumab in select advanced solid tumors: A phase 2 randomized trial","volume":"42","author":"Armstrong","year":"2024","journal-title":"Investig. New Drugs"},{"key":"ref_106","doi-asserted-by":"crossref","unstructured":"McCarthy, M.W., Chong, C., Riedemann, N.C., and Guo, R. (2025). A Targeted Blockade of Terminal C5a Is Critical to Management of Sepsis and Acute Respiratory Distress Syndrome: The Mechanism of Action of Vilobelimab. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26199628"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"e764","DOI":"10.1016\/S2665-9913(20)30341-6","article-title":"Anti-C5a antibody IFX-1 (vilobelimab) treatment versus best supportive care for patients with severe COVID-19 (PANAMO): An exploratory, open-label, phase 2 randomised controlled trial","volume":"2","author":"Vlaar","year":"2020","journal-title":"Lancet Rheumatol."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"e70194","DOI":"10.1002\/prp2.70194","article-title":"A Real-World Disproportionality Analysis of Avacopan in Anti-Neutrophil Cytoplasmic Antibodies Associated Vasculitis: Insights from FDA Adverse Event Reporting System","volume":"13","author":"Liang","year":"2025","journal-title":"Pharmacol. Res. Perspect."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"S9","DOI":"10.1016\/j.annonc.2022.01.023","article-title":"15P STELLAR-001: A phase I study of the anti-C5aR avdoralimab in combination with the anti-PD-L1 durvalumab in advanced solid tumors","volume":"33","author":"Bennouna","year":"2022","journal-title":"Ann. Oncol."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1016\/j.ccell.2022.04.010","article-title":"IL-6 blockade in cancer patients treated with immune checkpoint blockade: A win-win strategy","volume":"40","author":"Delyon","year":"2022","journal-title":"Cancer Cell"},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"9538","DOI":"10.1200\/JCO.2024.42.16_suppl.9538","article-title":"Interleukin-6 receptor blockade with tocilizumab to reduce immune-related toxicity with ipilimumab and nivolumab in metastatic melanoma","volume":"42","author":"Weber","year":"2024","journal-title":"J. Clin. Oncol."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"e008480","DOI":"10.1136\/jitc-2023-008480","article-title":"Efficacy, safety, and biomarker analyses of bintrafusp alfa, a bifunctional fusion protein targeting TGF-\u03b2 and PD-L1, in patients with advanced non-small cell lung cancer","volume":"12","author":"Rajan","year":"2024","journal-title":"J. Immunother. Cancer"},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"1731","DOI":"10.1016\/j.jtho.2023.08.018","article-title":"Bintrafusp Alfa Versus Pembrolizumab in Patients with Treatment-Naive, Programmed Death-Ligand 1-High Advanced NSCLC: A Randomized, Open-Label, Phase 3 Trial","volume":"18","author":"Cho","year":"2023","journal-title":"J. Thorac. Oncol."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"716","DOI":"10.1038\/s41591-024-02808-y","article-title":"Biomarker-directed targeted therapy plus durvalumab in advanced non-small-cell lung cancer: A phase 2 umbrella trial","volume":"30","author":"Besse","year":"2024","journal-title":"Nat. Med."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"TPS9600","DOI":"10.1200\/JCO.2022.40.16_suppl.TPS9600","article-title":"Tocilizumab in combination with ipilimumab and nivolumab in solid tumors","volume":"40","author":"Montazari","year":"2022","journal-title":"J. Clin. Oncol."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1038\/nchembio.1735","article-title":"Inhibition of PAD4 activity is sufficient to disrupt mouse and human NET formation","volume":"11","author":"Lewis","year":"2015","journal-title":"Nat. Chem. Biol."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"RP87030","DOI":"10.7554\/eLife.87030.4","article-title":"Anti-inflammatory therapy with nebulized dornase alfa for severe COVID-19 pneumonia: A randomized unblinded trial","volume":"12","author":"Porter","year":"2024","journal-title":"eLife"},{"key":"ref_118","unstructured":"(2026, March 04). ClinicalTrials.gov. Dornase Alfa and Cisplatin in Refractory Germ Cell Cancer. Identifier: NCT07121322, Available online: https:\/\/clinicaltrials.gov\/study\/NCT07121322."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1136\/annrheumdis-2024-eular.3510","article-title":"OP0110 AZD1163\u2014First-in-class anti-pad2\/4 bi-specific antibody to inhibit autoantigen formation in rheumatoid arthritis","volume":"83","author":"Sims","year":"2024","journal-title":"Ann. Rheum. Dis."},{"key":"ref_120","unstructured":"(2026, March 04). ClinicalTrials.gov. A Study to Investigate Efficacy and Safety of AZD1163 in Participants With Rheumatoid Arthritis (LaunchPAD-RA). Identifier: NCT07276581, Available online: https:\/\/clinicaltrials.gov\/study\/NCT07276581."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1007\/s00595-006-3409-0","article-title":"Neutrophil Elastase Inhibitor (Sivelestat) Preserves Antitumor Immunity and Reduces the Inflammatory Mediators Associated with Major Surgery","volume":"37","author":"Akamoto","year":"2007","journal-title":"Surg. Today"},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"524","DOI":"10.1016\/j.rmed.2012.12.009","article-title":"Phase II study of a neutrophil elastase inhibitor (AZD9668) in patients with bronchiectasis","volume":"107","author":"Stockley","year":"2013","journal-title":"Respir. Med."}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/16\/3\/400\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,10]],"date-time":"2026-03-10T05:24:24Z","timestamp":1773120264000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/16\/3\/400"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,8]]},"references-count":122,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2026,3]]}},"alternative-id":["biom16030400"],"URL":"https:\/\/doi.org\/10.3390\/biom16030400","relation":{},"ISSN":["2218-273X"],"issn-type":[{"value":"2218-273X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,8]]}}}