{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T15:17:37Z","timestamp":1785251857120,"version":"3.55.0"},"reference-count":48,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,4,14]],"date-time":"2026-04-14T00:00:00Z","timestamp":1776124800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of non-small cell lung cancer (NSCLC); however, their efficacy is confined to a subset of patients. The urgent development of biomarkers capable of predicting therapeutic efficacy prior to treatment is essential, as this could mitigate unnecessary adverse effects and reduce healthcare costs. In this study, we conducted an integrated lipidomic (phospholipid) and proteomic (whole serum and extracellular vesicle) analysis of pre-treatment serum samples obtained from patients with NSCLC who received nivolumab. The pre-treatment serum phospholipid profiles revealed significant differences between responder and non-responder groups. Notably, the lysophosphatidylcholine (LPC) class\u2014particularly LPC(20:0)\u2014emerged as a predictive biomarker, exhibiting elevated levels in responders (AUC = 0.782; LOOCV AUC = 0.720; Bootstrap AUC = 0.781). Proteomic analysis further indicated increased expression of complement components and acute-phase proteins in the non-responder group. Moreover, integration of serum, extracellular vesicle proteome, and phospholipid datasets using Weighted Gene Co-expression Network Analysis and Multi-Omics Factor Analysis suggested that biological processes potentially associated with LPC involve neutrophil and platelet activation pathways. Pre-treatment serum LPC levels are a promising biomarker for predicting the response to nivolumab therapy in NSCLC. This LPC signature reflects a systemic immunometabolic state involving platelet and neutrophil activity, suggesting a novel biological mechanism underlying ICI treatment efficacy.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1773700","type":"journal-article","created":{"date-parts":[[2026,4,14]],"date-time":"2026-04-14T04:21:56Z","timestamp":1776140516000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Identification of predictive biomarkers for nivolumab efficacy in non-small cell lung cancer through integrated serum lipidomics and proteomics analysis"],"prefix":"10.3389","volume":"17","author":[{"given":"Hiroaki","family":"Hase","sequence":"first","affiliation":[{"name":"Laboratory of Stem Cell Regeneration and Adaptation, Graduate School of Pharmaceutical Sciences, Osaka University","place":["Osaka, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshito","family":"Takeda","sequence":"additional","affiliation":[{"name":"Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, Osaka University","place":["Osaka, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shohei","family":"Koyama","sequence":"additional","affiliation":[{"name":"Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, Osaka University","place":["Osaka, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yujiro","family":"Naito","sequence":"additional","affiliation":[{"name":"Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, Osaka University","place":["Osaka, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kentaro","family":"Jingushi","sequence":"additional","affiliation":[{"name":"Laboratory of Stem Cell Regeneration and Adaptation, Graduate School of Pharmaceutical Sciences, Osaka University","place":["Osaka, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"So-Ichiro","family":"Fukada","sequence":"additional","affiliation":[{"name":"Laboratory of Stem Cell Regeneration and Adaptation, Graduate School of Pharmaceutical Sciences, Osaka University","place":["Osaka, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazutake","family":"Tsujikawa","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular and Cellular Physiology, Graduate School of Pharmaceutical Sciences, Osaka University","place":["Suita, Osaka, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,4,14]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1097\/CCO.0000000000000700","article-title":"Immunotherapy combinations in advanced nonsmall cell lung cancer","volume":"33","author":"Pirker","year":"2021","journal-title":"Curr Opin Oncol"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.3390\/cells11030320","article-title":"Immune checkpoint inhibitors in non-small cell lung cancer: Progress, challenges, and prospects","volume":"11","author":"Tang","year":"2022","journal-title":"Cells"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1038\/s41571-023-00794-7","article-title":"Immune-checkpoint inhibition for resectable non-small-cell lung cancer-opportunities and challenges","volume":"20","author":"Mountzios","year":"2023","journal-title":"Nat Rev Clin Oncol"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1111\/cas.15497","article-title":"Mechanisms of resistance to immune checkpoint inhibitors","volume":"113","author":"Nagasaki","year":"2022","journal-title":"Cancer Sci"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-pathol-042020-042741","article-title":"Immune checkpoint inhibitors for the treatment of cancer: Clinical impact and mechanisms of response and resistance","volume":"16","author":"Bagchi","year":"2021","journal-title":"Annu Rev Pathol"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1158\/2326-6066.CIR-20-0586","article-title":"Hallmarks of resistance to immune-checkpoint inhibitors","volume":"10","author":"Karasarides","year":"2022","journal-title":"Cancer Immunol Res"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1001\/jamanetworkopen.2023.52302","article-title":"Immune-related adverse events and survival among patients with metastatic NSCLC treated with immune checkpoint inhibitors","volume":"7","author":"Cook","year":"2024","journal-title":"JAMA Netw Open"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.24.00191","article-title":"Corticosteroids for immune-related adverse events and checkpoint inhibitor efficacy: Analysis of six clinical trials","volume":"42","author":"Verheijden","year":"2024","journal-title":"J Clin Oncol"},{"key":"B9","doi-asserted-by":"publisher","first-page":"6310","DOI":"10.1038\/s41598-025-91102-z","article-title":"Effects of immune related adverse events and corticosteroids on the outcome of patients treated with immune checkpoint inhibitors","volume":"15","author":"\u015een","year":"2025","journal-title":"Sci Rep"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1002\/cncr.32468","article-title":"Biomarkers for immune checkpoint inhibition in non-small cell lung cancer (NSCLC)","volume":"126","author":"Bodor","year":"2020","journal-title":"Cancer"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1016\/j.xcrm.2024.101621","article-title":"Advances and prospects of biomarkers for immune checkpoint inhibitors","volume":"5","author":"Yamaguch","year":"2024","journal-title":"Cell Rep Med"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1200\/PO.19.00171","article-title":"Harmonization of tumor mutational burden quantification and association with response to immune checkpoint blockade in non-small-cell lung cancer","volume":"3","author":"Vokes","year":"2019","journal-title":"JCO Precis Oncol"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1001\/jamaoncol.2022.1981","article-title":"Association of high tumor mutation burden in non-small cell lung cancers with increased immune infiltration and improved clinical outcomes of PD-L1 blockade across PD-L1 expression levels","volume":"8","author":"Ricciuti","year":"2022","journal-title":"JAMA Oncol"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1016\/j.critrevonc.2024.104332","article-title":"Circulating biomarkers as predictors of response to immune checkpoint inhibitors in NSCLC: Are we on the right path","volume":"197","author":"Spagnolo","year":"2024","journal-title":"Crit Rev Oncol Hematol"},{"key":"B15","doi-asserted-by":"publisher","first-page":"336","DOI":"10.1038\/s41392-024-02021-w","article-title":"Liquid biopsy in cancer current: status, challenges and future prospects","volume":"9","author":"Ma","year":"2024","journal-title":"Signal Transduct Targeted Ther"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1136\/jitc-2024-010824","article-title":"Modulating lipid metabolism improves tumor immunotherapy","volume":"13","author":"Ping","year":"2025","journal-title":"J Immunother Cancer"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1098\/rsob.240391","article-title":"Oxidized phospholipid damage signals as modulators of immunity","volume":"15","author":"Choi","year":"2025","journal-title":"Open Biol"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2025.118095","article-title":"Lipid metabolism in cancer: Exploring phospholipids as potential biomarkers","volume":"187","author":"Delmas","year":"2025","journal-title":"BioMed Pharmacother"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkae253","article-title":"MetaboAnalyst 6.0: towards a unified platform for metabolomics data processing, analysis and interpretation","volume":"52","author":"Pang","year":"2024","journal-title":"Nucleic Acids Res"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.3901","article-title":"The Perseus computational platform for comprehensive analysis of (prote)omics data","volume":"13","author":"Tyanova","year":"2016","journal-title":"Nat Methods"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jproteome.2c00513","article-title":"MS-DAP platform for downstream data analysis of label-free proteomics uncovers optimal workflows in benchmark data sets and increased sensitivity in analysis of Alzheimer's biomarker data","volume":"22","author":"Koopmans","year":"2023","journal-title":"J Proteome Res"},{"key":"B22","doi-asserted-by":"publisher","first-page":"1523","DOI":"10.1038\/s41467-019-09234-6","article-title":"Metascape provides a biologist-oriented resource for the analysis of systems-level datasets","volume":"10","author":"Zhou","year":"2019","journal-title":"Nat Commun"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.3390\/ijms26157528","article-title":"Plasma lysophosphatidylcholine levels correlate with prognosis and immunotherapy response in squamous cell carcinoma","volume":"26","author":"Iwasaki","year":"2025","journal-title":"Int J Mol Sci"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.3390\/ijms20051149","article-title":"An updated review of lysophosphatidylcholine metabolism in human diseases","volume":"20","author":"Law","year":"2019","journal-title":"Int J Mol Sci"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aaz6314","article-title":"Reprogramming lipid metabolism prevents effector T cell senescence and enhances tumor immunotherapy","volume":"13","author":"Liu","year":"2021","journal-title":"Sci Transl Med"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.21602","article-title":"Predictive clinical parameters for the response of nivolumab in pretreated advanced non-small-cell lung cancer","volume":"8","author":"Oya","year":"2017","journal-title":"Oncotarget"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.3390\/ijms26157528","article-title":"The lysophosphatidylcholine transporter MFSD2A is essential for CD8+ memory T cell maintenance and secondary response to infection","volume":"26","author":"Piccirillo","year":"2019","journal-title":"Int J Mol Sci"},{"key":"B28","doi-asserted-by":"publisher","first-page":"2024.08.07.24310974","DOI":"10.1101\/2024.08.07.24310974","article-title":"Linoleoyl-lysophosphatidylcholine suppresses immune-related adverse events due to immune checkpoint blockade","author":"Mathews","year":"2024","journal-title":"medRxiv"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2022.772076","article-title":"Acute phase proteins as early predictors for immunotherapy response in advanced NSCLC: An explorative study","volume":"12","author":"Schneider","year":"2022","journal-title":"Front Oncol"},{"key":"B30","doi-asserted-by":"publisher","first-page":"694","DOI":"10.1158\/2159-8290.CD-16-1184","article-title":"A combined PD-1\/C5a blockade synergistically protects against lung cancer growth and metastasis","volume":"7","author":"Ajona","year":"2017","journal-title":"Cancer Discov"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.3390\/biom13121803","article-title":"Neutrophil-to-lymphocyte ratio (NLR) in NSCLC, gastrointestinal, and other solid tumors: Immunotherapy and beyond","volume":"13","author":"Mosca","year":"2023","journal-title":"Biomolecules"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.3390\/biomedicines12081831","article-title":"Prognostic significance of plasma neutrophil extracellular trap levels in patients with non-small cell lung cancer treated with immune checkpoint inhibitors","volume":"12","author":"Horaguchi","year":"2024","journal-title":"Biomedicines"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.3390\/cancers16142507","article-title":"The multifaceted role of neutrophils in NSCLC in the era of immune checkpoint inhibitors","volume":"16","author":"Miao","year":"2024","journal-title":"Cancers (Basel)"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2022.941914","article-title":"Lysophosphatidylcholine alleviates acute lung injury by regulating neutrophil motility and neutrophil extracellular trap formation","volume":"10","author":"Jeong","year":"2022","journal-title":"Front Cell Dev Biol"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.174.5.2981","article-title":"Lysophosphatidylcholine modulates neutrophil oxidant production through elevation of cyclic AMP","volume":"174","author":"Lin","year":"2005","journal-title":"J Immunol"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0268288","article-title":"Prognostic value of the platelet-to-lymphocyte ratio in lung cancer patients receiving immunotherapy: A systematic review and meta-analysis","volume":"17","author":"Wang","year":"2022","journal-title":"PloS One"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1055\/s-0039-1683409","article-title":"Lysophosphatidylcholine is a major component of platelet microvesicles promoting platelet activation and reporting atherosclerotic plaque instability","volume":"119","author":"Diehl","year":"2019","journal-title":"Thromb Haemost"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1002\/cbin.12192","article-title":"Lysophosphatidylcholine induces oxidative stress and calcium-mediated cell death in human blood platelets","volume":"48","author":"Yadav","year":"2024","journal-title":"Cell Biol Int"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1096\/fj.11-191593","article-title":"Activated platelets contribute to oxidized low-density lipoproteins and dysfunctional high-density lipoproteins through a phospholipase A2-dependent mechanism","volume":"26","author":"Blache","year":"2012","journal-title":"FASEB J"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1038\/s41568-019-0116-x","article-title":"The evolving landscape of biomarkers for checkpoint inhibitor immunotherapy","volume":"19","author":"Havel","year":"2019","journal-title":"Nat Rev Cancer"},{"key":"B41","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1126\/science.aan4236","article-title":"Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients","volume":"359","author":"Gopalakrishnan","year":"2018","journal-title":"Science"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1126\/science.abl3656","article-title":"How microbiota improve immunotherapy","volume":"373","author":"Ansaldo","year":"2021","journal-title":"Science"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.3390\/cancers12123574","article-title":"Metabolomics to assess response to immune checkpoint inhibitors in patients with non-small-cell lung cancer","volume":"12","author":"Ghini","year":"2020","journal-title":"Cancers"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1016\/j.drup.2024.101159","article-title":"Comprehensive metabolomic analysis identifies key biomarkers and modulators of immunotherapy response in NSCLC patients","volume":"77","author":"Lee","year":"2024","journal-title":"Drug Resist Update"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2024.1348164","article-title":"Plasma lipidomics profiling in predicting the chemo-immunotherapy response in advanced non-small cell lung cancer","volume":"14","author":"Jiang","year":"2024","journal-title":"Front Oncol"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.MCT-23-0459","article-title":"Evaluating for correlations between specific metabolites in patients receiving first-line or second-line immunotherapy for metastatic or recurrent NSCLC: An exploratory study based on two cohorts","volume":"23","author":"Xu","year":"2024","journal-title":"Mol Cancer Ther"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2021.732319","article-title":"Phospholipases and reactive oxygen species derived lipid biomarkers in healthy and diseased humans and animals-a focus on lysophosphatidylcholine","volume":"12","author":"Engel","year":"2021","journal-title":"Front Physiol"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2023.5355","article-title":"Ziritaxestat, a novel autotaxin inhibitor, and lung function in idiopathic pulmonary fibrosis: The ISABELA 1 and 2 randomized clinical trials","volume":"329","author":"Maher","year":"2023","journal-title":"JAMA"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1773700\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,14]],"date-time":"2026-04-14T04:21:58Z","timestamp":1776140518000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1773700\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,14]]},"references-count":48,"alternative-id":["10.3389\/fimmu.2026.1773700"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2026.1773700","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,14]]},"article-number":"1773700"}}