Multi-omics characterization of C4orf19 in HNSCC: constructing prognostic signatures for immunotherapy and chemotherapy response prediction

C4orf19, a protein encoded by an open reading frame on human chromosome 4, exhibits aberrant expression in various tumors and is linked to patient prognosis, though its role in head and neck squamous cell carcinoma (HNSCC) remains unclear. TCGA and GEO datasets were analyzed to evaluate the prognostic value of C4orf19 in HNSCC. Functional assays (EdU, immunofluorescence, and CCK-8) were used to assess the effects of C4orf19 knockdown on tumor cell proliferation. Drug sensitivity analyses using the GDSC database and 5-fluorouracil (5-FU) chemosensitization experiments were performed. Bioinformatics approaches (CIBERSORT, ssGSEA, xCell, and maftools) were applied to explore associations between C4orf19 expression, the tumor microenvironment (TME), immune checkpoints, and tumor mutational burden (TMB). C4orf19 was downregulated in HNSCC patients and was associated with a poor prognosis. While C4orf19 knockdown did not affect proliferation of HNSCC cells, it enhanced 5-FU sensitivity. Mechanistically, C4orf19 may influence immunotherapy efficacy by modulating immune checkpoint gene expression, remodeling TME, and regulating TMB. These findings suggest that C4orf19 expression may serve as a predictive biomarker for immunotherapy response in HNSCC patients. C4orf19 expression shows potential as a predictive biomarker for immunotherapy response in HNSCC patients. The study highlights its role in enhancing chemosensitization and predicting immunotherapy efficacy, positioning C4orf19 as a promising prognostic biomarker and therapeutic predictor in HNSCC.