{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T23:06:16Z","timestamp":1788995176682,"version":"build-2803163510"},"reference-count":24,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T00:00:00Z","timestamp":1788998400000},"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. Genet."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Hypopharyngeal squamous cell carcinoma (HPSCC) carries the worst prognosis among head-and-neck cancers, with a 5-year overall survival of only 30%\u201335%. Despite ionizing radiation as the cornerstone of organ-preserving management, locoregional recurrence affects approximately half of patients. The molecular radiobiology of HPSCC\u2014encompassing DNA damage response (DDR), hypoxia-CAIX signaling, and cancer-associated fibroblast (CAF) remodeling\u2014has not been characterized at single-cell resolution or integrated into a validated precision radiotherapy prognostic model.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>GBD 2021 epidemiology data were analyzed. scRNA-seq datasets from treatment-na\u00efve Hypopharyngeal squamous cell carcinoma (GSE234933; cross-validation: GSE185206, GSE164690) were processed with Seurat and hdWGCNA. Additional hdWGCNA analyses were applied to the cancer-associated fibroblast and macrophage compartments. LASSO-penalized Cox regression of TCGA-HNSC Hypopharyngeal carcinoma bulk RNA-seq yielded a 9-gene prognostic signature, independently validated in GSE65858. A nomogram was constructed and evaluated by decision curve analysis. CIBERSORT quantified immune microenvironment composition, and qRT-PCR validated signature genes in HPC cell lines under 6\u00a0Gy irradiation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>hdWGCNA resolved 22 malignant epithelial modules; M1 (DDR\/ATM), M6 (hypoxia-CAIX-LDHA), and M22 (POLQ-SLFN11) showed dominant radiation-response enrichment. Additional hdWGCNA analyses identified Module C3 (CAF-stromal) and Mac2 (immunosuppressive macrophage). LASSO-Cox regression yielded the 9-gene signature (ATM, BRCA1, HIF1A, CA9, LDHA, TP53, SLFN11, POLQ, CDKN1A); bootstrap-corrected AUCs of 0.824\/0.793\/0.761 (1-\/3-\/5-year) in TCGA-HNSC were independently reproduced in GSE65858. High-risk patients showed an immunologically cold microenvironment, and qRT-PCR confirmed differential radiation-driven signature gene activation in contrasting-radiosensitivity HPC cell lines.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>This multi-omics study establishes a validated 9-gene precision radiotherapy prognostic signature for HPSCC, integrating single-cell-resolved mechanistic programs across the hypoxia-CAIX axis, the DDR-ATM-BRCA1 axis, and the POLQ-mediated alternative end-joining radioresistance axis as high-priority theranostic targets. Prospective multicenter clinical validation is mandated before nomogram deployment.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fgene.2026.1932515","type":"journal-article","created":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T22:10:18Z","timestamp":1788991818000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Integrating single-cell multi-omics for precision radiotherapy stratification in hypopharyngeal squamous cell carcinoma"],"prefix":"10.3389","volume":"17","author":[{"given":"Weishi","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Otolaryngology, Nantong First People\u2019s Hospital","place":["Nantong, Jiangsu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mei","family":"Yao","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology, Nantong First People\u2019s Hospital","place":["Nantong, Jiangsu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,10]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"42","DOI":"10.3390\/medsci11020042","article-title":"Epidemiology, risk factors, and prevention of head and neck squamous cell carcinoma","volume":"11","author":"Barsouk","year":"2023","journal-title":"Med. 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