{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T16:14:43Z","timestamp":1785428083409,"version":"3.56.0"},"reference-count":37,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2026,5,7]],"date-time":"2026-05-07T00:00:00Z","timestamp":1778112000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004861","name":"Hsinchu MacKay Memorial Hospital","doi-asserted-by":"publisher","award":["MMH-HB-11507"],"award-info":[{"award-number":["MMH-HB-11507"]}],"id":[{"id":"10.13039\/501100004861","id-type":"DOI","asserted-by":"publisher"}]},{"award":["MMH-HB-11507"],"award-info":[{"award-number":["MMH-HB-11507"]}],"id":[{"id":"https:\/\/ror.org\/015b6az38","id-type":"ROR","asserted-by":"publisher"}]},{"name":"the National Science and Technology Council","award":["NSTC 114-2221-E-195-001"],"award-info":[{"award-number":["NSTC 114-2221-E-195-001"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>This study aimed to develop and validate a transcriptomic risk signature for uterine corpus endometrial carcinoma (UCEC) and to investigate whether the identified prognostic program reflects immune\u2013tumor uncoupling within the tumor microenvironment. Using transcriptomic data from The Cancer Genome Atlas (TCGA) UCEC cohort, we identified a 28-gene transcriptomic signature defining a high-risk state. The derived risk score robustly stratified patients into distinct survival groups and remained an independent predictor of overall survival after adjustment for clinical covariates. Functional analyses revealed that high-risk tumors are characterized by a distinct immune\u2013tumor uncoupling phenotype, in which interferon-gamma (IFNG)-associated inflammatory signaling is preserved but fails to translate into effective antitumor immune activity. Specifically, effector immune programs, including CD8 T cell-related signatures and cytotoxic activity, were consistently reduced despite elevated IFNG-associated signaling, indicating a functional discordance between immune activation and immune execution rather than classical T cell exhaustion. In parallel, high-risk tumors exhibited consistently elevated cell cycle and DNA repair-associated transcriptional programs, suggesting that proliferative and stress-adaptive mechanisms represent dominant drivers of poor prognosis. External assessment in an independent GEO cohort (GSE17025) demonstrated consistent associations between signature activity, tumor status, and histological grade, supporting the reproducibility of the underlying transcriptional program at the biological and clinicopathological level. Collectively, this study provides transcriptomic evidence for a previously underappreciated immune\u2013tumor uncoupling state in UCEC and highlights the importance of integrating immune signaling and tumor-intrinsic programs to understand disease progression.<\/jats:p>","DOI":"10.3390\/ijms27104170","type":"journal-article","created":{"date-parts":[[2026,5,7]],"date-time":"2026-05-07T14:05:46Z","timestamp":1778162746000},"page":"4170","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Transcriptomic Evidence of Immune\u2013Tumor Uncoupling Defines a High-Risk State in Uterine Corpus Endometrial Carcinoma"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0222-6081","authenticated-orcid":false,"given":"Chia-Hung","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Medical Research, Hsinchu MacKay Memorial Hospital, Hsinchu 30071, Taiwan"},{"name":"Department of Medical Research, Hsinchu Municipal MacKay Children\u2019s Hospital, Hsinchu 30068, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui-Ju","family":"Kao","sequence":"additional","affiliation":[{"name":"Department of Medical Research, Hsinchu MacKay Memorial Hospital, Hsinchu 30071, Taiwan"},{"name":"Department of Medical Research, Hsinchu Municipal MacKay Children\u2019s Hospital, Hsinchu 30068, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2948-1824","authenticated-orcid":false,"given":"Chen-Lin","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Medical Research, Hsinchu MacKay Memorial Hospital, Hsinchu 30071, Taiwan"},{"name":"Department of Medical Research, Hsinchu Municipal MacKay Children\u2019s Hospital, Hsinchu 30068, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tzu-Hsiang","family":"Weng","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, MacKay Memorial Hospital, Taipei 10449, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tsung-Tao","family":"Huang","sequence":"additional","affiliation":[{"name":"National Center for Instrumentation Research, National Institutes of Applied Research, Hsinchu 30076, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9855-1035","authenticated-orcid":false,"given":"Kai-Yao","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Medical Research, Hsinchu MacKay Memorial Hospital, Hsinchu 30071, Taiwan"},{"name":"Department of Medical Research, Hsinchu Municipal MacKay Children\u2019s Hospital, Hsinchu 30068, Taiwan"},{"name":"Department of Medicine, MacKay Medical University, New Taipei 25245, Taiwan"},{"name":"Institute of Biomedical Sciences, MacKay Medical University, New Taipei 25245, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shun-Long","family":"Weng","sequence":"additional","affiliation":[{"name":"Department of Medicine, MacKay Medical University, New Taipei 25245, Taiwan"},{"name":"Department of Biological Science and Technology, College of Engineering Bioscience, National Yang Ming Chiao Tung University, Hsinchu 30068, Taiwan"},{"name":"Department of Obstetrics and Gynecology, Hsinchu MacKay Memorial Hospital, Hsinchu 30071, Taiwan"},{"name":"Department of Obstetrics and Gynecology, Hsinchu Municipal MacKay Children\u2019s Hospital, Hsinchu 30068, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1002\/ijgo.70326","article-title":"Cancer of the corpus uteri: A 2025 update","volume":"171","author":"Koskas","year":"2025","journal-title":"Int. J. Gynaecol. Obstet."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"781","DOI":"10.1038\/s41571-024-00934-7","article-title":"Translating biological insights into improved management of endometrial cancer","volume":"21","author":"How","year":"2024","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"e2443198","DOI":"10.1001\/jamanetworkopen.2024.43198","article-title":"Global Disparities of Cancer and Its Projected Burden in 2050","volume":"7","author":"Bizuayehu","year":"2024","journal-title":"JAMA Netw. Open"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"04155","DOI":"10.7189\/jogh.14.04155","article-title":"Global burden of gynaecological cancers in 2022 and projections to 2050","volume":"14","author":"Zhu","year":"2024","journal-title":"J. Glob. Health"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1962","DOI":"10.1038\/s41591-024-02993-w","article-title":"Prediction of recurrence risk in endometrial cancer with multimodal deep learning","volume":"30","author":"Horeweg","year":"2024","journal-title":"Nat. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"717","DOI":"10.1136\/ijgc-2020-001241","article-title":"Clinical patterns and genomic profiling of recurrent \u2018ultra-low risk\u2019 endometrial cancer","volume":"30","author":"Stasenko","year":"2020","journal-title":"Int. J. Gynecol. Cancer"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1038\/nature12113","article-title":"Integrated genomic characterization of endometrial carcinoma","volume":"497","author":"Kandoth","year":"2013","journal-title":"Nature"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"e85","DOI":"10.3802\/jgo.2023.34.e85","article-title":"FIGO staging of endometrial cancer: 2023","volume":"34","author":"Berek","year":"2023","journal-title":"J. Gynecol. Oncol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1016\/j.semcancer.2020.09.007","article-title":"Transcriptomics and solid tumors: The next frontier in precision cancer medicine","volume":"84","author":"Tsimberidou","year":"2022","journal-title":"Semin. Cancer Biol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"541","DOI":"10.1186\/s12935-020-01560-w","article-title":"Identification of an immune gene signature for predicting the prognosis of patients with uterine corpus endometrial carcinoma","volume":"20","author":"Zhou","year":"2020","journal-title":"Cancer Cell Int."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"45448","DOI":"10.1038\/s41598-025-28415-6","article-title":"A novel zinc finger protein gene signature for prognostic prediction, tumor microenvironment characterization, and therapeutic response in uterine corpus endometrial carcinoma","volume":"15","author":"Lv","year":"2025","journal-title":"Sci. Rep."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Emmert-Streib, F., Manjang, K., Dehmer, M., Yli-Harja, O., and Auvinen, A. (2021). Are There Limits in Explainability of Prognostic Biomarkers? Scrutinizing Biological Utility of Established Signatures. Cancers, 13.","DOI":"10.3390\/cancers13205087"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1038\/s41598-020-79375-y","article-title":"Prognostic gene expression signatures of breast cancer are lacking a sensible biological meaning","volume":"11","author":"Manjang","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Qian, Y., Daza, J., Itzel, T., Betge, J., Zhan, T., Marme, F., and Teufel, A. (2021). Prognostic Cancer Gene Expression Signatures: Current Status and Challenges. Cells, 10.","DOI":"10.3390\/cells10030648"},{"key":"ref_15","first-page":"e92707","article-title":"Tumor Microenvironment and Its Role in Cancer Progression: An Integrative Review","volume":"17","author":"Almazrouei","year":"2025","journal-title":"Cureus"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/j.ygyno.2023.01.037","article-title":"Impact of immune infiltration signatures on prognosis in endometrial carcinoma is dependent on the underlying molecular subtype","volume":"171","author":"Dessources","year":"2023","journal-title":"Gynecol. Oncol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"BSR20202321","DOI":"10.1042\/BSR20202321","article-title":"The landscape and prognostic value of immune characteristics in uterine corpus endometrial cancer","volume":"41","author":"Liu","year":"2021","journal-title":"Biosci. Rep."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/j.immuni.2013.07.008","article-title":"The continuum of cancer immunosurveillance: Prognostic, predictive, and mechanistic signatures","volume":"39","author":"Galon","year":"2013","journal-title":"Immunity"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1038\/nature12634","article-title":"Mutational landscape and significance across 12 major cancer types","volume":"502","author":"Kandoth","year":"2013","journal-title":"Nature"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1038\/bjc.2015.190","article-title":"A clinically applicable molecular-based classification for endometrial cancers","volume":"113","author":"Talhouk","year":"2015","journal-title":"Br. J. Cancer"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1016\/j.jare.2024.12.004","article-title":"Unlocking biological insights from differentially expressed genes: Concepts, methods, and future perspectives","volume":"76","author":"Yin","year":"2025","journal-title":"J. Adv. Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1565","DOI":"10.1126\/science.1203486","article-title":"Cancer immunoediting: Integrating immunity\u2019s roles in cancer suppression and promotion","volume":"331","author":"Schreiber","year":"2011","journal-title":"Science"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"812","DOI":"10.1016\/j.immuni.2018.03.023","article-title":"The Immune Landscape of Cancer","volume":"48","author":"Thorsson","year":"2018","journal-title":"Immunity"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1038\/nature21349","article-title":"Elements of cancer immunity and the cancer-immune set point","volume":"541","author":"Chen","year":"2017","journal-title":"Nature"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Leitao, B.N., Verissimo, A., Carvalho, A.M., and Vinga, S. (2025). Enhancing Prognostic Signatures in Glioblastoma with Feature Selection and Regularised Cox Regression. Genes, 16.","DOI":"10.3390\/genes16050473"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Haury, A.C., Gestraud, P., and Vert, J.P. (2011). The influence of feature selection methods on accuracy, stability and interpretability of molecular signatures. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0028210"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"189162","DOI":"10.1016\/j.bbcan.2024.189162","article-title":"T cell exhaustion in human cancers","volume":"1879","author":"Kang","year":"2024","journal-title":"Biochim. Biophys. Acta Rev. Cancer"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1038\/s41392-025-02327-3","article-title":"Revitalizing T cells: Breakthroughs and challenges in overcoming T cell exhaustion","volume":"11","author":"Wu","year":"2026","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"156046","DOI":"10.1016\/j.prp.2025.156046","article-title":"The paradoxical role of IFN-gamma in cancer: Balancing immune activation and immune evasion","volume":"272","author":"Liu","year":"2025","journal-title":"Pathol. Res. Pract."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1158\/2159-8290.CD-21-1059","article-title":"Hallmarks of Cancer: New Dimensions","volume":"12","author":"Hanahan","year":"2022","journal-title":"Cancer Discov."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1488","DOI":"10.2174\/1386207325666221005122554","article-title":"Identification of EMT-associated LncRNA Signature for Predicting the Prognosis of Patients with Endometrial Cancer","volume":"26","author":"Shu","year":"2023","journal-title":"Comb. Chem. High Throughput Screen."},{"key":"ref_32","first-page":"7191","article-title":"Expression of EZH2 in endometrial carcinoma and its effects on proliferation and invasion of endometrial carcinoma cells","volume":"14","author":"Gu","year":"2017","journal-title":"Oncol. Lett."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Verma, S., Goyal, N., Goyal, S., Kaur, P., and Gupta, S. (2025). EZH2 Dysregulation and Its Oncogenic Role in Human Cancers. Cancers, 17.","DOI":"10.3390\/cancers17193111"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"606","DOI":"10.1016\/j.trecan.2016.09.001","article-title":"The Emerging Role of Cdk5 in Cancer","volume":"2","author":"Pozo","year":"2016","journal-title":"Trends Cancer"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"17373","DOI":"10.18632\/oncotarget.14538","article-title":"Biological functions of CDK5 and potential CDK5 targeted clinical treatments","volume":"8","author":"Shupp","year":"2017","journal-title":"Oncotarget"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"550","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":"ref_37","doi-asserted-by":"crossref","first-page":"453","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"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/10\/4170\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,29]],"date-time":"2026-05-29T17:36:28Z","timestamp":1780076188000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/10\/4170"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,7]]},"references-count":37,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2026,5]]}},"alternative-id":["ijms27104170"],"URL":"https:\/\/doi.org\/10.3390\/ijms27104170","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,7]]}}}