{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,7]],"date-time":"2026-11-07T18:38:11Z","timestamp":1794076691104,"version":"4.8.0"},"reference-count":43,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T00:00:00Z","timestamp":1783382400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Duke Kunshan University Summer Research Scholars Program"},{"id":[{"id":"https:\/\/ror.org\/04sr5ys16","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100015671","name":"Jiangsu Provincial University Key (Construction) Laboratory for Smart Diagnosis and Treatment of Lung Cancer","doi-asserted-by":"publisher","award":["26KINFD011"],"award-info":[{"award-number":["26KINFD011"]}],"id":[{"id":"10.13039\/501100015671","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Life"],"abstract":"<jats:p>Blood-based biomarkers have emerged as promising, minimally invasive tools for the diagnosis, prognostic stratification, and treatment monitoring of non-small cell lung cancer (NSCLC), including markers of tumor burden, tumor dissemination, immune signaling, and post-transcriptional regulation. However, evidence across biomarker classes remains fragmented. This study aimed to synthesize published evidence on major blood-based biomarkers relevant to diagnosis, prognosis, treatment stratification, and monitoring in NSCLC. PubMed was searched for systematic reviews and meta-analyses of blood-based biomarkers in NSCLC. Of 356 screened records, 82 underwent full-text review, and 57 systematic reviews\/meta-analyses were included. Biomarkers were grouped into four categories: circulating tumor DNA (ctDNA), circulating tumor cells (CTCs), cytokines\/soluble immune proteins, and non-coding RNAs (ncRNAs). Reported pooled effect estimates were extracted by biomarker class and evidence domain, and the methodological quality of included reviews was assessed using AMSTAR 2. Evidence was unevenly distributed across biomarker classes and evidence domains. Circulating ncRNAs were mainly represented in diagnostic and prognostic evidence; selected diagnostic ncRNAs, including miR-145, miR-25, and circRNAs, showed reported AUCs ranging from 0.83 to 0.85. ctDNA was represented across diagnostic, prognostic, treatment-stratification, and dynamic monitoring evidence, with ctDNA positivity associated with poorer survival or recurrence outcomes and ctDNA clearance or decline associated with improved outcomes. CTC evidence was primarily prognostic, with CTC positivity associated with worse overall survival and disease-free survival. Soluble immune biomarker evidence was also primarily prognostic, with elevated soluble PD-L1 and IL-6 associated with adverse survival outcomes and limited exploratory monitoring evidence for exosomal PD-L1. Overall, the evidence suggested distinct but complementary roles across biomarker classes, although direct head-to-head comparisons were lacking. Blood-based biomarkers show potential to support diagnosis, prognosis, and longitudinal monitoring in NSCLC, but their reported utility differs by biomarker class and clinical context. In the available review-level evidence, ncRNAs were mainly represented in diagnostic and prognostic evidence, while ctDNA was represented across diagnostic, prognostic, treatment-stratification, and dynamic monitoring evidence. CTCs were mainly represented in prognostic evidence, and soluble immune biomarkers were primarily represented in prognostic evidence, with limited exploratory evidence for dynamic monitoring. Further assay standardization, prospective validation, and direct comparative studies are needed before these biomarkers can be routinely integrated into clinical practice.<\/jats:p>","DOI":"10.3390\/life16071130","type":"journal-article","created":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T09:53:46Z","timestamp":1783418026000},"page":"1130","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Diagnostic and Prognostic Roles of Blood-Based Immune Biomarkers in Non-Small Cell Lung Cancer: An Umbrella Review of Systematic Reviews and Meta-Analyses"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-6946-5921","authenticated-orcid":false,"given":"Panpinhan","family":"Zhao","sequence":"first","affiliation":[{"name":"Division of Natural and Applied Science, Duke Kunshan University, Suzhou 215316, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-3224-0865","authenticated-orcid":false,"given":"Rui","family":"Ling","sequence":"additional","affiliation":[{"name":"Division of Natural and Applied Science, Duke Kunshan University, Suzhou 215316, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruitong","family":"Li","sequence":"additional","affiliation":[{"name":"Division of Natural and Applied Science, Duke Kunshan University, Suzhou 215316, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8360-9537","authenticated-orcid":false,"given":"Yiu-Wing","family":"Kam","sequence":"additional","affiliation":[{"name":"Division of Natural and Applied Science, Duke Kunshan University, Suzhou 215316, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1297","DOI":"10.37349\/etat.2024.00277","article-title":"Addressing the unmet need in NSCLC progression with advances in second-line therapeutics","volume":"5","author":"Wang","year":"2024","journal-title":"Explor. Target. Anti-Tumor Ther."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"584","DOI":"10.1016\/S0025-6196(11)60735-0","article-title":"Non-small Cell Lung cancer: Epidemiology, Risk factors, treatment, and Survivorship","volume":"83","author":"Molina","year":"2008","journal-title":"Mayo Clin. Proc."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"975","DOI":"10.21037\/tlcr-24-979","article-title":"Recent advancements in lung cancer research: A narrative review","volume":"14","author":"Tang","year":"2025","journal-title":"Transl. Lung Cancer Res."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Oh, H.J., Imam-Aliagan, A.B., Kim, Y.B., Kim, H.J., Izaguirre, I.A., Sung, C.K., and Yim, H. (2024). Clinical applications of circulating biomarkers in non-small cell lung cancer. Front. Cell Dev. Biol., 12.","DOI":"10.3389\/fcell.2024.1449232"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"3241","DOI":"10.21037\/tlcr-24-828","article-title":"The latest advances in liquid biopsy for lung cancer\u2014A narrative review","volume":"13","author":"She","year":"2024","journal-title":"Transl. Lung Cancer Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1038\/nrc3775","article-title":"Non-small-cell Lung cancers: A Heterogeneous Set of Diseases","volume":"14","author":"Chen","year":"2014","journal-title":"Nat. Rev. Cancer"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"5563746","DOI":"10.1155\/2021\/5563746","article-title":"Role of Cytokines and Chemokines in NSCLC Immune Navigation and Proliferation","volume":"2021","author":"Ramachandran","year":"2021","journal-title":"Oxidative Med. Cell. Longev."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Wang, Q., He, Y., Li, W., Xu, X., Hu, Q., Bian, Z., Xu, A., Tu, H., Wu, M., and Wu, X. (2022). Soluble Immune Checkpoint-Related Proteins in Blood Are Associated with Invasion and Progression in Non-Small Cell Lung Cancer. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.887916"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"69174","DOI":"10.18632\/oncotarget.20088","article-title":"Long non-coding RNAs associated with non-small cell lung cancer","volume":"8","author":"Zhan","year":"2017","journal-title":"Oncotarget"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1007\/s12672-023-00686-3","article-title":"Circulating noncoding RNAs: Promising biomarkers in liquid biopsy for the diagnosis, prognosis, and therapy of NSCLC","volume":"14","author":"Li","year":"2023","journal-title":"Discov. Oncol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"100399","DOI":"10.1016\/j.esmoop.2022.100399","article-title":"Recommendations for a practical implementation of circulating tumor DNA mutation testing in metastatic non-small-cell lung cancer","volume":"7","author":"Heitzer","year":"2022","journal-title":"ESMO Open"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1416","DOI":"10.1016\/j.chest.2018.08.1048","article-title":"Immune Checkpoint Immunotherapy for Non-Small Cell Lung Cancer","volume":"154","author":"Suresh","year":"2018","journal-title":"Chest"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"3820956","DOI":"10.1155\/2018\/3820956","article-title":"Anti-PD-1\/PD-L1 Antibody Therapy for Pretreated Advanced or Metastatic Nonsmall Cell Lung Carcinomas and the Correlation between PD-L1 Expression and Treatment Effectiveness: An Update Meta-Analysis of Randomized Clinical Trials","volume":"2018","author":"Zhao","year":"2018","journal-title":"BioMed Res. Int."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"422","DOI":"10.1093\/oncolo\/oyae006","article-title":"Impact of Increasing PD-L1 Levels on Outcomes to PD-1\/PD-L1 Inhibition in Patients With NSCLC: A Pooled Analysis of 11 Prospective Clinical Trials","volume":"29","author":"Vallejo","year":"2024","journal-title":"Oncologist"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"278","DOI":"10.1186\/s40425-019-0768-9","article-title":"The role of PD-L1 expression as a predictive biomarker: An analysis of all US Food and Drug Administration (FDA) approvals of immune checkpoint inhibitors","volume":"7","author":"Davis","year":"2019","journal-title":"J. Immunother. Cancer"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1016\/j.intonc.2025.05.001","article-title":"A narrative review of the prediction of immunotherapy efficacy for treating NSCLC: An artificial intelligence perspective","volume":"1","author":"Wu","year":"2025","journal-title":"Intell. Oncol."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Liberini, V., Mariniello, A., Righi, L., Capozza, M., Delcuratolo, M.D., Terreno, E., Farsad, M., Volante, M., Novello, S., and Deandreis, D. (2021). NSCLC Biomarkers to Predict Response to Immunotherapy with Checkpoint Inhibitors (ICI): From the Cells to In Vivo Images. Cancers, 13.","DOI":"10.20944\/preprints202108.0372.v1"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1186\/s13046-024-02969-1","article-title":"Blood-based biomarkers in patients with non-small cell lung cancer treated with immune checkpoint blockade","volume":"43","author":"Tsai","year":"2024","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Rother, C., John, T., and Wong, A. (2024). Biomarkers for immunotherapy resistance in non-small cell lung cancer. Front. Oncol., 14.","DOI":"10.3389\/fonc.2024.1489977"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"n71","DOI":"10.1136\/bmj.n71","article-title":"The PRISMA 2020 statement: An updated guideline for reporting systematic reviews","volume":"372","author":"Page","year":"2021","journal-title":"Br. Med. J."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"j4008","DOI":"10.1136\/bmj.j4008","article-title":"AMSTAR 2: A Critical Appraisal Tool for Systematic Reviews That Include Randomised or non-randomised Studies of Healthcare interventions, or Both","volume":"358","author":"Shea","year":"2017","journal-title":"BMJ"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1177\/1724600820967124","article-title":"Circulating microRNA-145 as a diagnostic biomarker for non-small-cell lung cancer: A systemic review and meta-analysis","volume":"35","author":"Tao","year":"2020","journal-title":"Int. J. Biol. Markers"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"e23425\u20135","DOI":"10.1097\/MD.0000000000023425","article-title":"Diagnostic value of microRNA-25 in patients with non-small cell lung cancer in Chinese population","volume":"99","author":"Li","year":"2020","journal-title":"Medicine"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Yu, W., Liu, R., Miao, Z., Zhang, L., Sheyhidin, I., and Ainiwaer, J. (2022). The diagnostic significance of blood-derived circRNAs in NSCLC: Systematic review and meta-analysis. Front. Oncol., 12.","DOI":"10.3389\/fonc.2022.987704"},{"key":"ref_25","unstructured":"Pop-Bica, C., Pintea, S., Lorand Magdo Cojocneanu, R., Gulei, D., Ferracin, M., and Berindan-Neagoe, I. (2020). The Clinical Utility of miR-21 and let-7 in Non-small Cell Lung Cancer (NSCLC). A Systematic Review and Meta-Analysis. Front. Oncol., 10."},{"key":"ref_26","first-page":"4166","article-title":"Elevated miR-21 is associated with poor prognosis in non-small cell lung cancer: A systematic review and meta-analysis","volume":"22","author":"Yuan","year":"2018","journal-title":"Eur. Rev. Med. Pharmacol. Sci."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"11377","DOI":"10.18632\/oncotarget.23994","article-title":"Long non-coding RNAs function as novel predictors and targets of non-small cell lung cancer: A systematic review and meta-analysis","volume":"9","author":"Xiong","year":"2018","journal-title":"Oncotarget"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1007\/s40291-024-00725-x","article-title":"Clinical Validity and Utility of Circulating Tumor DNA (ctDNA) Testing in Advanced Non-small Cell Lung Cancer (aNSCLC): A Systematic Literature Review and Meta-analysis","volume":"28","author":"Chen","year":"2024","journal-title":"Mol. Diagn. Ther."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1621","DOI":"10.1007\/s10238-022-00924-y","article-title":"Clinical significance of circulating tumor DNA in localized non-small cell lung cancer: A systematic review and meta-analysis","volume":"23","author":"Guo","year":"2022","journal-title":"Clin. Exp. Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"3641","DOI":"10.3390\/cancers16213641","article-title":"The Evidence Base for Circulating Tumor DNA-Methylation in Non-Small Cell Lung Cancer: A Systematic Review and Meta-Analysis","volume":"16","author":"Maffeo","year":"2024","journal-title":"Cancers"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1007\/s00432-023-05550-z","article-title":"Prognostic value of preoperative circulating tumor DNA in non-small cell lung cancer: A systematic review and meta-analysis","volume":"150","author":"Lu","year":"2024","journal-title":"J. Cancer Res. Clin. Oncol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"571","DOI":"10.1080\/07357907.2023.2220820","article-title":"The Utility of ctDNA in Lung Cancer Clinical Research and Practice: A Systematic Review and Meta-Analysis of Clinical Studies","volume":"41","author":"Sun","year":"2023","journal-title":"Cancer Investig."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"17588359231177008","DOI":"10.1177\/17588359231177008","article-title":"Prognostic value of postoperative ctDNA detection in patients with early non-small cell lung cancer: A systematic review and meta-analysis","volume":"15","author":"Guo","year":"2023","journal-title":"Ther. Adv. Med. Oncol."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Durgesh Wankhede Grover, S., and Hofman, P. (2022). Circulating Tumor Cells as a Predictive Biomarker in Resectable Lung Cancer: A Systematic Review and Meta-Analysis. Cancers, 14.","DOI":"10.3390\/cancers14246112"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"14496","DOI":"10.3390\/ijms232214496","article-title":"Soluble PD-L1 as a Prognostic Factor for Immunotherapy Treatment in Solid Tumors: Systematic Review and Meta-Analysis","volume":"23","author":"Scirocchi","year":"2022","journal-title":"Int. J. Mol. Sci."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"318","DOI":"10.1186\/s12957-023-03215-2","article-title":"Prognostic significance of blood-based PD-L1 analysis in patients with non-small cell lung cancer undergoing immune checkpoint inhibitor therapy: A systematic review and meta-analysis","volume":"21","author":"Cui","year":"2023","journal-title":"World J. Surg. Oncol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"469","DOI":"10.3233\/CBM-140423","article-title":"Prognostic value of circulating inflammatory factors in non-small cell lung cancer: A systematic review and meta-analysis","volume":"14","author":"Liao","year":"2014","journal-title":"Cancer Biomark."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Wang, X., Bai, L., Kong, L., and Guo, Z. (2024). Advances in circulating tumor cells for early detection, prognosis and metastasis reduction in lung cancer. Front. Oncol., 14.","DOI":"10.3389\/fonc.2024.1411731"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/bs.ircmb.2024.03.001","article-title":"Circulating tumor cells in lung cancer: Integrating stemness and heterogeneity to improve clinical utility","volume":"392","author":"Beninato","year":"2025","journal-title":"Int. Rev. Cell Mol. Biol."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Chrzempiec, M., and Oleksiewicz, U. (2026). Circulating Tumor Cells for the Monitoring of Lung Cancer Therapies. Int. J. Mol. Sci., 27.","DOI":"10.3390\/ijms27010384"},{"key":"ref_41","doi-asserted-by":"crossref","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. Target. Ther."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1038\/s41698-025-00984-9","article-title":"A comprehensive overview of minimal residual disease in the management of early-stage and locally advanced non-small cell lung cancer","volume":"9","author":"Boukouris","year":"2025","journal-title":"npj Precis. Oncol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1038\/s41698-025-00876-y","article-title":"Circulating tumor DNA to monitor treatment response in solid tumors and advance precision oncology","volume":"9","author":"Bartolomucci","year":"2025","journal-title":"npj Precis. Oncol."}],"container-title":["Life"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2075-1729\/16\/7\/1130\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T11:07:27Z","timestamp":1783422447000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2075-1729\/16\/7\/1130"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,7]]},"references-count":43,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2026,7]]}},"alternative-id":["life16071130"],"URL":"https:\/\/doi.org\/10.3390\/life16071130","relation":{},"ISSN":["2075-1729"],"issn-type":[{"value":"2075-1729","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,7]]}}}