{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T11:44:49Z","timestamp":1787312689519,"version":"build-2736575974"},"reference-count":39,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2026,5,15]],"date-time":"2026-05-15T00:00:00Z","timestamp":1778803200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Key Research and Development Program of China","award":["2025YFC3508300"],"award-info":[{"award-number":["2025YFC3508300"]}]},{"name":"National Key Research and Development Program of China","award":["2025YFC3508301"],"award-info":[{"award-number":["2025YFC3508301"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background: Small cell lung cancer (SCLC) carries a dismal prognosis with limited biomarkers for risk stratification. This study aimed to identify circulating prognostic biomarkers. Methods: We prioritized SCLC risk-associated genes using Summary-data-based Mendelian Randomization of pQTL\/eQTL, differential expression, and weighted gene co-expression network analysis. Five machine learning approaches were compared to develop a diagnostic model based on ACE, AGER, and IL18R1, trained on GSE149507 and validated in GSE60052. We conducted single-cell transcriptomic analysis using public datasets (GSE150766 and GSE279570) and peripheral blood mononuclear cells (PBMCs) from our extensive-stage cohort. Finally, prioritizing the lead candidate IL18R1, we enrolled a prospective clinical cohort to assess its prognostic utility. A LASSO\u2013Cox prognostic model incorporating plasma IL18R1 and clinical variables was internally validated (7:3 split) for progression-free survival (PFS) prediction. Results: Integrative multi-omics identified ACE, AGER, and IL18R1 as SCLC-protective genes. Elastic Net machine learning identified a two-gene predictive signature (AGER and IL18R1) with robust diagnostic accuracy. Single-cell RNA sequencing revealed the predominant downregulation of ACE, AGER, and IL18R1 in T cells and alveolar type II cells from SCLC patients. PBMC analysis further supported IL18R1 downregulation in CD8+ T cells, NK cells, and dendritic cells. In an independent prospective cohort (n = 300), lower plasma IL18R1 levels were independently associated with shorter PFS (HR = 0.997 per unit increase; 95% CI: 0.995\u20130.999; and p = 0.003), with time-dependent AUCs of 0.77\u20130.86. Performance in limited-stage disease was inconsistent and requires further validation. A prognostic model incorporating plasma IL18R1 and 11 clinical parameters stratified patients into distinct risk groups (HR = 5.19), showing a strong discriminative ability in extensive-stage SCLC. Conclusions: We identified ACE, AGER, and IL18R1 as protective factors against SCLC progression. Integration of plasma IL18R1 with clinical parameters provides a prognostic tool for extensive-stage SCLC.<\/jats:p>","DOI":"10.3390\/cancers18101608","type":"journal-article","created":{"date-parts":[[2026,5,15]],"date-time":"2026-05-15T10:33:21Z","timestamp":1778841201000},"page":"1608","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Integrative Multi-Omics Analysis Identifies IL18R1 as a Circulating Prognostic Biomarker for Risk Stratification in Extensive-Stage Small Cell Lung Cancer"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1007-5562","authenticated-orcid":false,"given":"Shengjuan","family":"Hu","sequence":"first","affiliation":[{"name":"Department of Hematology and Oncology, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing 100700, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6414-6645","authenticated-orcid":false,"given":"Sicong","family":"Li","sequence":"additional","affiliation":[{"name":"Traditional Chinese Medicine Department, National Cancer Center\/National Clinical Research Center for Cancer\/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiyuan","family":"Cui","sequence":"additional","affiliation":[{"name":"Traditional Chinese Medicine Department, National Cancer Center\/National Clinical Research Center for Cancer\/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Oncology, The Mongolia-Chinese Medical Hospital of Chifeng, Chifeng 024000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luyao","family":"Chen","sequence":"additional","affiliation":[{"name":"The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou 511436, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiyuan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Traditional Chinese Medicine Department, National Cancer Center\/National Clinical Research Center for Cancer\/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Hou","sequence":"additional","affiliation":[{"name":"Department of Hematology and Oncology, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing 100700, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Feng","sequence":"additional","affiliation":[{"name":"Traditional Chinese Medicine Department, National Cancer Center\/National Clinical Research Center for Cancer\/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China"},{"name":"Beijing Key Laboratory of Digital Intelligence Traditional Chinese Medicine Oncology Prevention and Treatment, Beijing 100021, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,15]]},"reference":[{"key":"ref_1","first-page":"620","article-title":"Clinical Insights into Small Cell Lung Cancer: Tumor Heterogeneity, Diagnosis, Therapy, and Future Directions","volume":"73","author":"Megyesfalvi","year":"2023","journal-title":"CA Cancer J. Clin."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1016\/j.cllc.2021.09.003","article-title":"Current Strategies for Extensive Stage Small Cell Lung Cancer Beyond First-Line Therapy","volume":"23","author":"Hao","year":"2022","journal-title":"Clin. Lung Cancer"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"100408","DOI":"10.1016\/j.esmoop.2022.100408","article-title":"Durvalumab, with or without Tremelimumab, plus Platinum-Etoposide in First-Line Treatment of Extensive-Stage Small-Cell Lung Cancer: 3-Year Overall Survival Update from CASPIAN","volume":"7","author":"Chen","year":"2022","journal-title":"ESMO Open"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1038\/nature14664","article-title":"Comprehensive Genomic Profiles of Small Cell Lung Cancer","volume":"524","author":"George","year":"2015","journal-title":"Nature"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1429","DOI":"10.1016\/j.jtho.2021.07.012","article-title":"All That Glitters Is Not Gold: The Story of Rovalpituzumab Tesirine in SCLC","volume":"16","author":"Uprety","year":"2021","journal-title":"J. Thorac. Oncol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2063","DOI":"10.1056\/NEJMoa2307980","article-title":"Tarlatamab for Patients with Previously Treated Small-Cell Lung Cancer","volume":"389","author":"Ahn","year":"2023","journal-title":"N. Engl. J. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1038\/ng.3538","article-title":"Integration of Summary Data from GWAS and eQTL Studies Predicts Complex Trait Gene Targets","volume":"48","author":"Zhu","year":"2016","journal-title":"Nat. Genet."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"508","DOI":"10.1038\/s41586-022-05473-8","article-title":"FinnGen Provides Genetic Insights from a Well-Phenotyped Isolated Population","volume":"613","author":"Kurki","year":"2023","journal-title":"Nature"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1300","DOI":"10.1038\/s41588-021-00913-z","article-title":"Large-Scale Cis- and Trans-eQTL Analyses Identify Thousands of Genetic Loci and Polygenic Scores That Regulate Blood Gene Expression","volume":"53","author":"Claringbould","year":"2021","journal-title":"Nat. Genet."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Folkersen, L., Fauman, E., Sabater-Lleal, M., Strawbridge, R.J., Fr\u00e5nberg, M., Sennblad, B., Baldassarre, D., Veglia, F., Humphries, S.E., and Rauramaa, R. (2017). Mapping of 79 Loci for 83 Plasma Protein Biomarkers in Cardiovascular Disease. PLoS Genet., 13.","DOI":"10.1371\/journal.pgen.1006706"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"14357","DOI":"10.1038\/ncomms14357","article-title":"Connecting Genetic Risk to Disease End Points through the Human Blood Plasma Proteome","volume":"8","author":"Suhre","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"769","DOI":"10.1126\/science.aaq1327","article-title":"Co-Regulatory Networks of Human Serum Proteins Link Genetics to Disease","volume":"361","author":"Emilsson","year":"2018","journal-title":"Science"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1038\/s41586-018-0175-2","article-title":"Genomic Atlas of the Human Plasma Proteome","volume":"558","author":"Sun","year":"2018","journal-title":"Nature"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"3268","DOI":"10.1038\/s41467-018-05512-x","article-title":"Genome-Wide Mapping of Plasma Protein QTLs Identifies Putatively Causal Genes and Pathways for Cardiovascular Disease","volume":"9","author":"Yao","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"1000 Genomes Project Consortium, Auton, A., Brooks, L.D., Durbin, R.M., Garrison, E.P., Kang, H.M., Korbel, J.O., Marchini, J.L., McCarthy, S., and McVean, G.A. (2015). A Global Reference for Human Genetic Variation. Nature, 526, 68\u201374.","DOI":"10.1038\/nature15393"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1189\/jlb.5RU0816-341R","article-title":"A Protective Role of IL-37 in Cancer: A New Hope for Cancer Patients","volume":"101","author":"Abulkhir","year":"2017","journal-title":"J. Leukoc. Biol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"394","DOI":"10.1016\/j.smim.2013.10.023","article-title":"The Interleukin-1 Receptor Family","volume":"25","author":"Boraschi","year":"2013","journal-title":"Semin. Immunol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"695","DOI":"10.1016\/j.tcb.2020.06.003","article-title":"The Roles of CD8+ T Cell Subsets in Antitumor Immunity","volume":"30","author":"Ohashi","year":"2020","journal-title":"Trends Cell Biol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2394","DOI":"10.1158\/0008-5472.CAN-15-1548","article-title":"Inflammation-Dependent IL18 Signaling Restricts Hepatocellular Carcinoma Growth by Enhancing the Accumulation and Activity of Tumor-Infiltrating Lymphocytes","volume":"76","author":"Markowitz","year":"2016","journal-title":"Cancer Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"e1328337","DOI":"10.1080\/2162402X.2017.1328337","article-title":"IL-18 Receptor Marks Functional CD8+ T Cells in Non-Small Cell Lung Cancer","volume":"6","author":"Timperi","year":"2017","journal-title":"Oncoimmunology"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Guo, Q., Wu, C.-Y., Jiang, N., Tong, S., Wan, J.-H., Xiao, X.-Y., Mei, P.-Y., Liu, H.-S., and Wang, S.-H. (2022). Downregulation of T-Cell Cytotoxic Marker IL18R1 Promotes Cancer Proliferation and Migration and Is Associated with Dismal Prognosis and Immunity in Lung Squamous Cell Carcinoma. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.986447"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Fenini, G., Contassot, E., and French, L.E. (2017). Potential of IL-1, IL-18 and Inflammasome Inhibition for the Treatment of Inflammatory Skin Diseases. Front. Pharmacol., 8.","DOI":"10.3389\/fphar.2017.00278"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"593","DOI":"10.1089\/10799900252982070","article-title":"The Combination of Soluble IL-18R\u03b1 and IL-18R\u03b2 Chains Inhibits IL-18-Induced IFN- \u03b3","volume":"22","author":"Reznikov","year":"2002","journal-title":"J. Interferon Cytokine Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"10344","DOI":"10.1038\/s41467-025-65262-5","article-title":"High Expression of Interleukin-18 Receptor Alpha Correlates with Severe Respiratory Viral Disease and Defines T Cells with Reduced Cytotoxic Signatures","volume":"16","author":"Cabug","year":"2025","journal-title":"Nat. Commun."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"3320","DOI":"10.1021\/acs.jproteome.3c00389","article-title":"IL18R1-Related Molecules as Biomarkers for Asthma Severity and Prognostic Markers for Idiopathic Pulmonary Fibrosis","volume":"22","author":"Lin","year":"2023","journal-title":"J. Proteome Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1824","DOI":"10.1056\/NEJMoa2408771","article-title":"Enhanced CAR T-Cell Therapy for Lymphoma after Previous Failure","volume":"392","author":"Svoboda","year":"2025","journal-title":"N. Engl. J. Med."},{"key":"ref_27","first-page":"501","article-title":"Aminopeptidases and Angiotensin I-Converting Enzyme Activities in Primary Human Lung Tumors and Lung Parenchyma","volume":"38","author":"Krepela","year":"1991","journal-title":"Neoplasma"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Danilov, S.M., Metzger, R., Klieser, E., Sotlar, K., Trakht, I.N., and Garcia, J.G.N. (2019). Tissue ACE Phenotyping in Lung Cancer. PLoS ONE, 14.","DOI":"10.1371\/journal.pone.0226553"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Yao, T., Wu, Z., Wang, Z., Chen, L., Liu, B., Lu, M., and Shen, N. (2023). Association between Angiotensin-Converting Enzyme Inhibitor-Induced Cough and the Risk of Lung Cancer: A Mendelian Randomization Study. Front. Pharmacol., 14.","DOI":"10.3389\/fphar.2023.1267924"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"917108","DOI":"10.1155\/2010\/917108","article-title":"The Receptor for Advanced Glycation End Products (RAGE) and the Lung","volume":"2010","author":"Buckley","year":"2010","journal-title":"J. Biomed. Biotechnol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1093\/carcin\/bgh333","article-title":"Down-Regulation of the Receptor for Advanced Glycation End-Products (RAGE) Supports Non-Small Cell Lung Carcinoma","volume":"26","author":"Bartling","year":"2005","journal-title":"Carcinogenesis"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1007\/s00441-005-0069-0","article-title":"Promotion of Cell Adherence and Spreading: A Novel Function of RAGE, the Highly Selective Differentiation Marker of Human Alveolar Epithelial Type I Cells","volume":"323","author":"Demling","year":"2006","journal-title":"Cell Tissue Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1038\/s41419-020-2432-1","article-title":"RAGE Acts as an Oncogenic Role and Promotes the Metastasis of Human Lung Cancer","volume":"11","author":"Chen","year":"2020","journal-title":"Cell Death Dis."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"188556","DOI":"10.1016\/j.bbcan.2021.188556","article-title":"Tumor Suppressor P53: Biology, Signaling Pathways, and Therapeutic Targeting","volume":"1876","author":"Borrero","year":"2021","journal-title":"Biochim. Biophys. Acta Rev. Cancer"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"635","DOI":"10.1038\/s41577-023-00849-x","article-title":"The NLR Gene Family: From Discovery to Present Day","volume":"23","author":"Chou","year":"2023","journal-title":"Nat. Rev. Immunol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1186\/s12964-019-0459-7","article-title":"Hedgehog\/GLI Signaling in Tumor Immunity\u2014New Therapeutic Opportunities and Clinical Implications","volume":"17","author":"Stockmaier","year":"2019","journal-title":"Cell Commun. Signal"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1016\/j.lungcan.2019.05.004","article-title":"Inhibition of the Hedgehog Pathway in Lung Cancer","volume":"133","author":"Dimou","year":"2019","journal-title":"Lung Cancer"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1504","DOI":"10.1038\/nm.2473","article-title":"A Crucial Requirement for Hedgehog Signaling in Small Cell Lung Cancer","volume":"17","author":"Park","year":"2011","journal-title":"Nat. Med."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1038\/nature01493","article-title":"Hedgehog Signalling within Airway Epithelial Progenitors and in Small-Cell Lung Cancer","volume":"422","author":"Watkins","year":"2003","journal-title":"Nature"}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/18\/10\/1608\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,17]],"date-time":"2026-05-17T04:14:01Z","timestamp":1778991241000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/18\/10\/1608"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,15]]},"references-count":39,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2026,5]]}},"alternative-id":["cancers18101608"],"URL":"https:\/\/doi.org\/10.3390\/cancers18101608","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,15]]}}}