ArticleFrontiers in genetics2026
Integrating single-cell multi-omics for precision radiotherapy stratification in hypopharyngeal squamous cell carcinoma.
Article in Frontiers in genetics, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Background: Hypopharyngeal squamous cell carcinoma (HPSCC) carries the worst prognosis among head-and-neck cancers, with a 5-year overall survival of only 30%-35%. Despite ionizing radiation as the cornerstone of organ-preserving management, locoregional recurrence affects approximately half of patients. The molecular radiobiology of HPSCC-encompassing DNA damage response (DDR), hypoxia-CAIX signaling, and cancer-associated fibroblast (CAF) remodeling-has not been characterized at single-cell resolution or integrated into a validated precision radiotherapy prognostic model. Methods: GBD 2021 epidemiology data were analyzed. scRNA-seq datasets from treatment-naïve 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 Gy irradiation. Results: 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. Conclusion: 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.
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