{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T18:03:29Z","timestamp":1790100209458,"version":"4.0.1"},"reference-count":28,"publisher":"Public Library of Science (PLoS)","issue":"9","license":[{"start":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T00:00:00Z","timestamp":1790035200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Fujian Provincial Natural Science Foundation Program Project","award":["2025J01884"],"award-info":[{"award-number":["2025J01884"]}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:p>Immune checkpoint inhibitors benefit only a subset of patients with urothelial carcinoma, and bulk biomarkers may not capture spatially organized stromal and vascular programs that restrict immune access. We performed a retrospective public multi-cohort transcriptomic study to examine whether a cancer-associated fibroblast (CAF)\/TGF-beta\/endothelial barrier direction is associated with immune exclusion and checkpoint resistance in bladder cancer. GSE171351 was used for spatial discovery, GSE319536 for external spatial recurrence testing, TCGA-BLCA for prognosis-oriented support, and IMvigor210, GSE176307 and GSE328930\/DUTRENEO for treatment-response projection. In the four-section discovery cohort, rank-5 non-negative matrix factorization separated an E2 barrier-enriched program from an E4 hypoxic epithelial program, although component assignment was strongly associated with section identity. The external cohort reproduced the direct CAF\/TGF-beta\/endothelial barrier direction in 22 of 22 sections but did not reproduce E2\/E4 mutual exclusivity: projected E2 and E4 were positively correlated (rho\u2009=\u20090.928). In IMvigor210, top-quartile E2-high tumors showed suggestive, but not statistically conclusive, evidence of anti-PD-L1 non-response after full biologic covariate adjustment (OR=2.57, 95% CI 1.00\u20136.64, p\u2009=\u20090.051; delta AUC\u2009=\u20090.009). A prespecified heuristic barrier-exclusion score was associated with non-response in exploratory fixed- and random-effects summaries (OR=1.52, 95% CI 1.20\u20131.92), including a sensitivity analysis excluding GSE328930. These results identify a recurrent barrier direction rather than a universal two-niche architecture and support a hypothesis-generating mechanism-to-translation framework that requires prospective spatial and pathology-level validation.<\/jats:p>","DOI":"10.1371\/journal.pone.0358043","type":"journal-article","created":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T17:25:31Z","timestamp":1790097931000},"page":"e0358043","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["A recurrent cancer-associated fibroblast\/TGF-beta\/endothelial barrier direction is associated with immune exclusion and checkpoint resistance in bladder cancer: a public multi-cohort transcriptomic study"],"prefix":"10.1371","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-4895-8475","authenticated-orcid":true,"given":"Yuye","family":"Wu","sequence":"first","affiliation":[{"name":"The Second Affiliated Hospital of Fujian University of Traditional Chinese Medicine","place":["Fuzhou, China"],"department":["Department of Urology"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guangjie","family":"Li","sequence":"additional","affiliation":[{"name":"The Second Affiliated Hospital of Fujian University of Traditional Chinese Medicine","place":["Fuzhou, China"],"department":["Department of Urology"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lixing","family":"Jiang","sequence":"additional","affiliation":[{"name":"The Second Affiliated Hospital of Fujian University of Traditional Chinese Medicine","place":["Fuzhou, China"],"department":["Department of Urology"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chaohong","family":"Zhang","sequence":"additional","affiliation":[{"name":"The Second Affiliated Hospital of Fujian University of Traditional Chinese Medicine","place":["Fuzhou, China"],"department":["Department of Urology"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huilong","family":"Fang","sequence":"additional","affiliation":[{"name":"The Second Affiliated Hospital of Fujian University of Traditional Chinese Medicine","place":["Fuzhou, China"],"department":["Department of Urology"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haiqing","family":"Fan","sequence":"additional","affiliation":[{"name":"The Second Affiliated Hospital of Fujian University of Traditional Chinese Medicine","place":["Fuzhou, China"],"department":["Department of Urology"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2026,9,22]]},"reference":[{"issue":"1","key":"pone.0358043.ref001","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1038\/s41572-023-00468-9","article-title":"Bladder cancer","volume":"9","author":"L Dyrskj\u00f8t","year":"2023","journal-title":"Nat Rev Dis 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