{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T06:07:44Z","timestamp":1789106864426,"version":"build-2803163510"},"reference-count":32,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T00:00:00Z","timestamp":1789084800000},"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. Cell Dev. Biol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Interferon-responsive tumor-cell states can simultaneously increase immune visibility and induce immune-regulatory programs, yet their epithelial-cell distribution and treatment responsiveness in bladder cancer remain incompletely defined. We sought to resolve a reproducible epithelial interferon-response state across patients, characterize its immune context, and determine whether its transcriptional components respond to ionizing radiation\n                      <jats:italic>in vitro<\/jats:italic>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Single-cell RNA sequencing data from seven primary bladder tumors and one adjacent normal sample were reanalyzed with uniform quality control and doublet removal. After broad-lineage annotation, 29,777 identity-gated tumor epithelial cells were reclustered and analyzed by repeated non-negative matrix factorization across ranks and random seeds. An NMF-informed three-gene interferon-response score based on IFI27, ISG15, and IFI6 was used to define patient-internal upper- and lower-quartile states. Differential expression was assessed by patient-blocked pseudobulk edgeR models, followed by Hallmark, Gene Ontology, and Reactome enrichment, leave-one-patient-out analyses, immune-feature scoring, balanced CellChat analysis, and TCGA-BLCA corroboration. T24 bladder cancer cells were exposed to 0, 2, 4, or 8\u00a0Gy, and selected transcripts were quantified by qRT-PCR 24\u00a0h later.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>The final atlas comprised 39,224 cells assigned to six broad lineages. Repeated NMF reproducibly identified an IFI27-centered epithelial program, and the corresponding score showed marked interpatient variation while remaining detectable across all seven tumors. Patient-blocked analysis identified 179 genes with false-discovery rate &amp;lt;0.05 and absolute log2FC \u2265 0.5; IFIT1, CXCL10, IFI44L, IFITM1, HLA-B, B2M, CD74, IFI6, and ISG15 were representative upregulated genes. IFN-response-score-high epithelial cells showed strong enrichment of interferon-gamma response, interferon-alpha response, inflammatory response, IL6-JAK-STAT3 signaling, antigen processing and presentation, and chemokine-response programs. MHC-I, MHC-II, CXCL9\/10\/11-related, and immune-regulatory ligand scores increased in all seven patient-paired comparisons, whereas CD274 itself remained sparsely detected and was not stably associated with the continuous score. Balanced pooled CellChat analyses prioritized relatively enriched MDK-SDC1, MDK-SDC2, and MDK-ITGA6\/ITGB1 candidate interactions. TCGA-BLCA analyses corroborated the broader interferon and antigen-presentation context at gene and pathway levels. Irradiation induced dose-associated increases in IFI27, ISG15, IFI6, IFIT1, CXCL10, and IFITM1 transcripts, accompanied by increases in CD274, VIM, and SNAI1 and a decrease in CDH1.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Bladder tumors contain a reproducible IFI27-centered epithelial interferon-response state with coordinated antigen-presentation, chemokine-related, and selected immune-regulatory transcriptional features. Its molecular context is supported across patients and in bulk transcriptomes, while irradiation-associated qRT-PCR changes suggest that components of the program are treatment responsive. These findings define a hypothesis-generating epithelial immune state and candidate communication axes for future spatial, protein-level, and functional validation.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fcell.2026.1920354","type":"journal-article","created":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T05:30:27Z","timestamp":1789104627000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Single-cell and bulk transcriptomic analyses define an IFI27-centered interferon-response epithelial state in bladder cancer and its transcriptional response to irradiation"],"prefix":"10.3389","volume":"14","author":[{"given":"Yang","family":"Ji","sequence":"first","affiliation":[{"name":"Urology Department, East Hospital Area, Xinxiang Central Hospital","place":["Xinxiang, Henan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yangyang","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Urology, Xinxiang Central Hospital","place":["Xinxiang, Henan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaodong","family":"Liu","sequence":"additional","affiliation":[{"name":"The Fourth Clinical College of Henan Medical University, Henan Medical University","place":["Xinxiang, Henan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhuoyuan","family":"Lv","sequence":"additional","affiliation":[{"name":"The Fourth Clinical College of Henan Medical University, Henan Medical University","place":["Xinxiang, Henan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yakai","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Urology, Xinxiang Central Hospital","place":["Xinxiang, Henan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shixuan","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Urology, Xinxiang Central Hospital","place":["Xinxiang, Henan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Urology, Xinxiang Central Hospital","place":["Xinxiang, Henan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,11]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"2930","DOI":"10.1172\/JCI91190","article-title":"IFN-gamma-related mRNA profile predicts clinical response to PD-1 blockade","volume":"127","author":"Ayers","year":"2017","journal-title":"J. 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