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In this study, we first retrieved and harmonized single\u2010cell RNA sequencing (RNA\u2010Seq), bulk RNA\u2010Seq, and spatial transcriptomic profiles from public repositories. We then applied high\u2010dimensional weighted gene coexpression network analysis (hdWGCNA) and gene nonnegative matrix factorization (GeneNMF) to dissect HPV+ epithelial subpopulations, their extracellular matrix (ECM)\u2013interacting ligand programs, and CXCL\/complement immune circuits. Furthermore, we mapped the spatial niches of malignant and immune cells and constructed a consensus prognostic index using 101 machine learning algorithms. Our findings revealed transcriptionally distinct HPV+ epithelial clusters that activate viral oncogenesis, inflammatory pathways, and ECM\u2010sensing pathways. These cells communicate with stromal and immune compartments via CXCL axes and complement cascades, yet they are spatially segregated from lymphocytes. A high\u2010risk signature, identified as HPV\u2010related risk genes including TRMT112, stratified the TCGA\u2010HNSC and GSE65858 cohorts into patients with markedly worse 1\u2010, 2\u2010, and 3\u2010year survival rates (ROC\u2013AUC 0.934, 0.968, and 0.973) and poor responses to immunotherapy. Notably, TRMT112 expression inversely correlated with cytotoxic T\u2010cell infiltration, mechanistically linking it to the formation of \u201ccold\u201d tumors. Our integrative analysis defines HPV\u2010driven epithelial subpopulations whose TRMT112\u2010enriched, immune\u2010excluded microenvironment contributes to therapeutic resistance, thus providing robust prognostic biomarkers and actionable targets for precision immunotherapy in HPV+ HNSCC.<\/jats:p>","DOI":"10.1155\/humu\/5308441","type":"journal-article","created":{"date-parts":[[2025,11,5]],"date-time":"2025-11-05T05:36:32Z","timestamp":1762320992000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Multiomic Landscape Uncovers TRMT112 as a Central Driver of HPV\u2010Positive Head and Neck Squamous Cell Carcinoma"],"prefix":"10.1155","volume":"2025","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-5018-9309","authenticated-orcid":false,"given":"Tongnan","family":"Yin","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-7398-709X","authenticated-orcid":false,"given":"Qian","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-1757-9002","authenticated-orcid":false,"given":"Zhenwei","family":"Wen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1462-5330","authenticated-orcid":false,"given":"Yikun","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-6450-4123","authenticated-orcid":false,"given":"Chenwen","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-1367-2294","authenticated-orcid":false,"given":"Zhongyu","family":"Qu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,11,4]]},"reference":[{"key":"e_1_2_13_1_2","doi-asserted-by":"publisher","DOI":"10.3390\/biom11091293"},{"key":"e_1_2_13_2_2","doi-asserted-by":"publisher","DOI":"10.1111\/joim.13010"},{"key":"e_1_2_13_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41572-020-00224-3"},{"key":"e_1_2_13_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41416-019-0602-7"},{"key":"e_1_2_13_5_2","doi-asserted-by":"publisher","DOI":"10.3390\/cancers12051060"},{"key":"e_1_2_13_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41571-022-00603-7"},{"key":"e_1_2_13_7_2","first-page":"77","article-title":"New Insights Into Human Papillomavirus-Associated Head and Neck Squamous Cell Carcinoma","volume":"33","author":"Boscolo-Rizzo P.","year":"2013","journal-title":"Acta Otorhinolaryngologica Italica"},{"key":"e_1_2_13_8_2","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.32781"},{"key":"e_1_2_13_9_2","doi-asserted-by":"publisher","DOI":"10.1007\/s12672-025-02093-2"},{"key":"e_1_2_13_10_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrc2982"},{"key":"e_1_2_13_11_2","doi-asserted-by":"publisher","DOI":"10.1155\/2021\/1738932"},{"key":"e_1_2_13_12_2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.00653"},{"key":"e_1_2_13_13_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41746-025-01930-6"},{"key":"e_1_2_13_14_2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2025.1573815"},{"key":"e_1_2_13_15_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12943-024-02191-9"},{"key":"e_1_2_13_16_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkac947"},{"key":"e_1_2_13_17_2","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.3519"},{"key":"e_1_2_13_18_2","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.29649"},{"key":"e_1_2_13_19_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkv007"},{"key":"e_1_2_13_20_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-022-01141-9"},{"key":"e_1_2_13_21_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-023-06130-4"},{"key":"e_1_2_13_22_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-021-00894-z"},{"key":"e_1_2_13_23_2","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.4463"},{"key":"e_1_2_13_24_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/28.1.27"},{"key":"e_1_2_13_25_2","doi-asserted-by":"crossref","unstructured":"YuG. 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