{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T17:48:08Z","timestamp":1789753688993,"version":"4.0.1"},"reference-count":55,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,9,3]],"date-time":"2025-09-03T00:00:00Z","timestamp":1756857600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100017596","name":"Natural Science Basic Research Program of Shaanxi Province","doi-asserted-by":"publisher","award":["2022JM-446"],"award-info":[{"award-number":["2022JM-446"]}],"id":[{"id":"10.13039\/501100017596","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100015401","name":"Key Research and Development Projects of Shaanxi Province","doi-asserted-by":"publisher","award":["2022SF-041, 2022SF-159"],"award-info":[{"award-number":["2022SF-041, 2022SF-159"]}],"id":[{"id":"10.13039\/501100015401","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Papillary thyroid microcarcinoma (PTMC) with lateral neck lymph node involvement exhibits a deceptively indolent yet highly invasive phenotype, characterized by early dissemination and slow tumor growth. A comprehensive understanding of integrating multiomics landscapes, circulating immune profiles, and tumor immune microenvironment is essential for more accurate surveillance and tailored therapeutic strategies.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Clinical profile and circulating immune-inflammatory markers from 638 PTMC patients were analyzed using multivariate and least absolute shrinkage and selection operator (LASSO) regression to recognize N1b-associated risk indicators. Eight supervised machine learning models were trained via 10-fold cross-validation to select the optimal classifier. Weighted gene coexpression network analysis (WGCNA) alongside machine learning identified metastasis-related gene modules from the integrated RNA-seq profile, leading to a multilayer perceptron gene classifier. Genomic profiling was employed to investigate mutations, copy number alterations, and methylation modifications in signature genes, followed by screening of antineoplastic drugs and docking simulations to explore their therapeutic potential. CIBERSORT, combined with immunohistochemistry, was used to investigate immune infiltration and functional changes in N1b-stage PTMC lesions.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Two clinical metastasis risk models were developed, with Model A based on the neutrophil-to-lymphocyte ratio (NLR) and Model B on lymphocyte and neutrophil counts, where Model A showed superior generalization (AUC = 0.852) and discriminative performance. NLR was an independent risk determinant for N1b-stage PTMC (OR = 2.12, p &amp;lt; 0.01). Transcriptomic profiling revealed a molecular signature (\n                      <jats:italic>ALDH1A3<\/jats:italic>\n                      ,\n                      <jats:italic>CTXN1<\/jats:italic>\n                      ,\n                      <jats:italic>MGAT3<\/jats:italic>\n                      , and\n                      <jats:italic>TMEM163<\/jats:italic>\n                      ) of occult lateral lymph node metastasis, exhibiting strong robustness (AUC = 0.857). Signature genes were predominantly associated with cell adhesion, intercellular signaling, and KRAS dysregulation pathways. Hypomethylation of\n                      <jats:italic>CTXN1<\/jats:italic>\n                      ,\n                      <jats:italic>MGAT3<\/jats:italic>\n                      , and\n                      <jats:italic>TMEM163<\/jats:italic>\n                      may underlie transcriptional activation. N1b-stage tumors exhibited reduced CD8+ T and T follicular helper cell infiltration but increased dendritic,\n                      <jats:italic>\u03b3\u03b4<\/jats:italic>\n                      T, and activated CD4+ memory T cells, suggesting immune evasion and compensatory immune activation.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>This study constructed a robust metastasis prediction nomogram for N1b-stage PTMC and identified metastasis-associated molecular drivers through integrative multiomics analysis. Comprehensive profiling of systemic and tumor-infiltrating immunity revealed key antitumor immune alterations. These findings establish a framework for early metastatic phenotype detection, potentially inspiring relevant immunotherapeutic hypotheses.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2025.1620085","type":"journal-article","created":{"date-parts":[[2025,9,3]],"date-time":"2025-09-03T05:37:27Z","timestamp":1756877847000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":4,"title":["Multi-omics analysis and metastasis risk factor prediction in N1b stage PTMC: insights into immune infiltration and therapeutic implications"],"prefix":"10.3389","volume":"16","author":[{"given":"Hao","family":"Dai","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qian","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wanli","family":"Ren","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qian","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bei","family":"Pei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenyan","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiqian","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhihan","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinzi","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan","family":"Shao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiang","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanxia","family":"Bai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,9,3]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1089\/thy.2022.0723","article-title":"Inequities in thyroid cancer care: Populations most at risk for delays in diagnosis and treatment","volume":"33","author":"Lopez","year":"2023","journal-title":"Thyroid"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/S2213-8587(23)00094-3","article-title":"Effect of the covid19 pandemic on surgery for indeterminate thyroid nodules (thycovid): a retrospective, international, multicentre, cross-sectional study","volume":"11","author":"Medas","year":"2023","journal-title":"Lancet Diabetes Endocrinol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2023.26348","article-title":"Thyroid cancer: A review","volume":"331","author":"Boucai","year":"2024","journal-title":"JAMA"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/S2213-8587(22)00139-5","article-title":"Management of thyroid nodules","volume":"10","author":"Alexander","year":"2022","journal-title":"Lancet Diabetes Endocrinol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1016\/S2213-8587(22)00101-2","article-title":"Diagnosis of thyroid nodules","volume":"10","author":"Alexander","year":"2022","journal-title":"Lancet Diabetes Endocrinol"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1089\/thy.2022.0109","article-title":"Outcomes of papillary thyroid microcarcinoma presenting with palpable lateral lymphadenopathy","volume":"32","author":"Papachristos","year":"2022","journal-title":"Thyroid"},{"key":"B7","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1089\/thy.2015.0020","article-title":"2015 American thyroid association management guidelines for adult patients with thyroid nodules and differentiated thyroid cancer: the american thyroid association guidelines task force on thyroid nodules and differentiated thyroid cancer","volume":"26","author":"Haugen","year":"2016","journal-title":"Thyroid"},{"key":"B8","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/s12967-023-04045-2","article-title":"Multi-omics profiling of papillary thyroid microcarcinoma reveals different somatic mutations and a unique transcriptomic signature","volume":"21","author":"Li","year":"2023","journal-title":"J Trans Med"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1148\/radiol.230006","article-title":"Us predictors of papillary thyroid microcarcinoma progression at active surveillance","volume":"309","author":"Lee","year":"2023","journal-title":"Radiology"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1089\/thy.2022.0155","article-title":"A significance of concomitant brafv600e and tert mutations in polish patients with papillary thyroid microcarcinoma: A retrospective cohort study based on 430 cases","volume":"32","author":"Kuchareczko","year":"2022","journal-title":"Thyroid"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1007\/s40618-022-01960-x","article-title":"Identification of potential diagnostic and prognostic biomarkers for papillary thyroid microcarcinoma (ptmc) based on tmt-labeled lc\u2013ms\/ms and machine learning","volume":"46","author":"Li","year":"2023","journal-title":"J Endocrinological Invest"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1038\/s41388-022-02254-5","article-title":"Integrative metabolomic characterization identifies plasma metabolomic signature in the diagnosis of papillary thyroid cancer","volume":"41","author":"Yu","year":"2022","journal-title":"Oncogene"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijsu.2018.05.030","article-title":"Prognostic significance of lymphocyte to monocyte ratio in colorectal cancer: A meta-analysis","volume":"55","author":"Tan","year":"2018","journal-title":"Int J Surg"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1089\/thy.2018.0684","article-title":"Low lymphocyte-to-monocyte ratios are associated with poor overall survival in anaplastic thyroid carcinoma patients","volume":"29","author":"Ahn","year":"2019","journal-title":"Thyroid"},{"key":"B15","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/s12916-020-01817-1","article-title":"Neutrophil to lymphocyte ratio and cancer prognosis: an umbrella review of systematic reviews and meta-analyses of observational studies","volume":"18","author":"Cupp","year":"2020","journal-title":"BMC Med"},{"key":"B16","doi-asserted-by":"publisher","first-page":"106959","DOI":"10.1016\/j.ijsu.2022.106959","article-title":"Prognostic value of neutrophil-to-lymphocyte ratio in colorectal cancer liver metastasis: A meta-analysis of results from multivariate analysis","volume":"107","author":"Lin","year":"2022","journal-title":"Int J Surg"},{"key":"B17","doi-asserted-by":"publisher","first-page":"100995","DOI":"10.1016\/j.jhepr.2023.100995","article-title":"Predictive value of platelet-tolymphocyte and neutrophil-to-lymphocyte ratio in hcc treated with sorafenib and radioembolization","volume":"6","author":"\u00d6cal","year":"2024","journal-title":"JHEP Rep"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1007\/s11154-023-09845-x","article-title":"Preoperative systemic inflammatory markers as prognostic factors in differentiated thyroid cancer: a systematic review and meta-analysis","volume":"24","author":"Russo","year":"2023","journal-title":"Rev Endocrine Metab Disord"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.3390\/ijms232415626","article-title":"Association of brafv600e mutation with the aggressive behavior of papillary thyroid microcarcinoma: a meta-analysis of 33 studies","volume":"23","author":"Attia","year":"2022","journal-title":"Int J Mol Sci"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejca.2019.10.017","article-title":"Braf v600e status may facilitate decisionmaking on active surveillance of low-risk papillary thyroid microcarcinoma","volume":"124","author":"Kim","year":"2020","journal-title":"Eur J Cancer"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.3390\/ijms22041726","article-title":"A narrative review of genetic alterations in primary thyroid epithelial cancer","volume":"22","author":"Romei","year":"2021","journal-title":"Int J Mol Sci"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2014.09.050","article-title":"Integrated genomic characterization of papillary thyroid carcinoma","volume":"159","author":"Agrawal","year":"2014","journal-title":"Cell"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2006-0492","article-title":"Clinicopathological significance of major histocompatibility complex class i-related chain a and b expression in thyroid cancer","volume":"91","author":"Xu","year":"2006","journal-title":"J Clin Endocrinol Metab"},{"key":"B24","volume-title":"AJCC cancer staging manual","author":"Amin","year":"2017"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.3122","article-title":"Stringtie enables improved reconstruction of a transcriptome from rna-seq reads","volume":"33","author":"Pertea","year":"2015","journal-title":"Nat Biotechnol"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1002\/cam4.2544","article-title":"Extensive lymphatic spread of papillary thyroid microcarcinoma is associated with an increase in expression of genes involved in epithelial-mesenchymal transition and cancer stem cell-like properties","volume":"8","author":"Lee","year":"2019","journal-title":"Cancer Med"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1016\/j.gene.2021.146086","article-title":"Identification of key genes associated with papillary thyroid microcarcinoma characteristics by integrating transcriptome sequencing and weighted gene co-expression network analysis","volume":"811","author":"Yang","year":"2022","journal-title":"Gene"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1038\/s41587-020-0546-8","article-title":"Visualizing and interpreting cancer genomics data via the xena platform","volume":"38","author":"Goldman","year":"2020","journal-title":"Nat Biotechnol"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkv007","article-title":"limma powers differential expression analyses for rna-sequencing and microarray studies","volume":"43","author":"Ritchie","year":"2015","journal-title":"Nucleic Acids Res"},{"key":"B30","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/s13059-014-0550-8","article-title":"Moderated estimation of fold change and dispersion for rna-seq data with deseq2","volume":"15","author":"Love","year":"2014","journal-title":"Genome Biol"},{"key":"B31","doi-asserted-by":"publisher","first-page":"100141","DOI":"10.1016\/j.xinn.2021.100141","article-title":"clusterprofiler 4.0: A universal enrichment tool for interpreting omics data","volume":"2","author":"Wu","year":"2021","journal-title":"Innovation"},{"key":"B32","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/1471-2105-9-559","article-title":"Wgcna: an r package for weighted correlation network analysis","volume":"9","author":"Langfelder","year":"2008","journal-title":"BMC Bioinf"},{"key":"B33","doi-asserted-by":"publisher","first-page":"44","DOI":"10.1038\/nprot.2008.211","article-title":"Systematic and integrative analysis of large gene lists using david bioinformatics resources","volume":"4","author":"Huang","year":"2009","journal-title":"Nat Protoc"},{"key":"B34","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1023\/A:1010933404324","article-title":"Random forests","volume":"45","author":"Breiman","year":"2001","journal-title":"Mach Learn"},{"key":"B35","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/1471-2105-14-7","article-title":"Gsva: gene set variation analysis for microarray and rna-seq data","volume":"14","author":"H\u00e4nzelmann","year":"2013","journal-title":"BMC Bioinf"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.3337","article-title":"Robust enumeration of cell subsets from tissue expression profiles","volume":"12","author":"Newman","year":"2015","journal-title":"Nat Methods"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2013.10.003","article-title":"Spatiotemporal dynamics of intratumoral immune cells reveal the immune landscape in human cancer","volume":"39","author":"Bindea","year":"2013","journal-title":"Immunity"},{"key":"B38","doi-asserted-by":"publisher","first-page":"130663","DOI":"10.1016\/j.bbagen.2024.130663","article-title":"The k346t mutant of gnt-iii bearing weak in vitro and potent intracellular activity","volume":"1868","author":"Hashimoto","year":"2024","journal-title":"Biochim Biophys Acta (BBA)-General Subj"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1016\/j.canlet.2015.08.018","article-title":"Aldehyde dehydrogenases and cancer stem cells","volume":"369","author":"Xu","year":"2015","journal-title":"Cancer Lett"},{"key":"B40","first-page":"1","article-title":"Enzyme targeting strategies for prevention and treatment of cancer: Implications for cancer therapy","volume-title":"Seminars in cancer biology","author":"Baig","year":"2019"},{"key":"B41","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/bcr3648","article-title":"Changes in aldehyde dehydrogenase-1 expression during neoadjuvant chemotherapy predict outcome in locally advanced breast cancer","volume":"16","author":"Alamgeer","year":"2014","journal-title":"Breast Cancer Res"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1038\/s41388-020-1184-9","article-title":"Dual disruption of aldehyde dehydrogenases 1 and 3 promotes functional changes in the glutathione redox system and enhances chemosensitivity in nonsmall cell lung cancer","volume":"39","author":"Rebollido-Rios","year":"2020","journal-title":"Oncogene"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-10-1994","article-title":"Tumorigenic and metastatic activity of human thyroid cancer stem cells","volume":"70","author":"Todaro","year":"2010","journal-title":"Cancer Res"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1016\/j.ab.2019.113389","article-title":"Kad\u0131oglu\u02d8 Y, Salih B. N-glycan profiling of papillary thyroid carcinoma tissues by maldi-tof-ms","volume":"584","author":"Ko\u00e7ak","year":"2019","journal-title":"Analytical Biochem"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1002\/bit.26496","article-title":"Modulation of igg1 immunoeffector function by glycoengineering of the gdp-fucose biosynthesis pathway","volume":"115","author":"Kelly","year":"2018","journal-title":"Biotechnol bioengineering"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1016\/j.jprot.2022.104700","article-title":"Site-specific n-glycosylation analysis of human thyroid thyroglobulin by mass spectrometry-based glyco-analytical strategies","volume":"267","author":"Kayili","year":"2022","journal-title":"J Proteomics"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1002\/mco2.458","article-title":"Identification of rp11-770j1. 4 as immune-related lncrna regulating the ctxn1\u2013cgas\u2013sting axis in histologically lower-grade glioma","volume":"4","author":"Zhuang","year":"2023","journal-title":"MedComm"},{"key":"B48","doi-asserted-by":"publisher","first-page":"154","DOI":"10.1038\/s41420-022-00938-1","article-title":"Tumor suppressive role of microrna-4731-5p in breast cancer through reduction of paics-induced fak phosphorylation","volume":"8","author":"Lang","year":"2022","journal-title":"Cell Death Discov"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1016\/j.abb.2019.108166","article-title":"Transmembrane 163 (tmem163) protein effluxes zinc","volume":"677","author":"Sanchez","year":"2019","journal-title":"Arch Biochem biophysics"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.3390\/nu9121286","article-title":"Zinc as a gatekeeper of immune function","volume":"9","author":"Wessels","year":"2017","journal-title":"Nutrients"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1161\/STROKEAHA.118.021179","article-title":"Synergistic interaction between zinc and reactive oxygen species amplifies ischemic brain injury in rats","volume":"49","author":"Zhao","year":"2018","journal-title":"Stroke"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M109.047696","article-title":"Src induces podoplanin expression to promote cell migration","volume":"285","author":"Shen","year":"2010","journal-title":"J Biol Chem"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2020.570604","article-title":"Immune cell confrontation in the papillary thyroid carcinoma microenvironment","volume":"11","author":"Xie","year":"2020","journal-title":"Front Endocrinol"},{"key":"B54","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1038\/s41419-020-03294-z","article-title":"A new risk factor indicator for papillary thyroid cancer based on immune infiltration","volume":"12","author":"Yang","year":"2021","journal-title":"Cell Death Dis"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.1038\/s41571-022-00722-1","article-title":"The emerging roles of \u03b3\u03b4 t cells in cancer immunotherapy","volume":"20","author":"Mensurado","year":"2023","journal-title":"Nat Rev Clin Oncol"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1620085\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,9,3]],"date-time":"2025-09-03T05:37:28Z","timestamp":1756877848000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1620085\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,3]]},"references-count":55,"alternative-id":["10.3389\/fimmu.2025.1620085"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2025.1620085","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,9,3]]},"article-number":"1620085"}}