A Comprehensive Analysis of Exosome-Related Long Noncoding RNAs as Prognostic Biomarkers and Therapeutic Targets in Head and Neck Squamous Cell Carcinoma

Background. Long noncoding RNAs (lncRNAs) often facilitate cellular communication via exosomes. However, their specific roles in head and neck squamous cell carcinoma (HNSCC) are not well understood. Methods. We extracted data on exosome-related lncRNAs from exoRBase and collected transcriptional profiles and clinical details for HNSCC from the TCGA database. Data preprocessing and analyses incorporated Tumor Mutation Burden and Microsatellite Instability from Researcher’s Home and drug sensitivity information from Genomics of Drug Sensitivity in Cancer database. We developed a prognostic model using Cox regression and LASSO regression analysis, with subsequent multivariate analysis to identify significant prognostic indicators. We also constructed a nomogram to evaluate the model’s clinical relevance, performed Gene Set Enrichment Analysis (GSEA), and analyzed the immune microenvironment and therapy sensitivity using CIBERSORT and TIDE algorithms. Supporting in vitro experiments and statistical analyses were conducted. Results. Our comprehensive investigation revealed 17 exosome-associated lncRNAs critical for patient survival in HNSCC. This enabled the development of a prognostic model that effectively stratifies patients into high-risk and low-risk categories. These lncRNAs correlate with patient demographics and clinical characteristics such as age, gender, and tumor stage. GSEA highlighted significant gene expression differences between the risk groups, particularly in pathways related to muscle formation, cellular transition, and immune response. The analysis of the immune microenvironment showed distinct immune cell infiltration patterns in high-risk patients, indicative of compromised immune defenses. In addition, we explored the expression of critical immune checkpoints and their impact on immunotherapy efficacy, demonstrating that risk scores may predict treatment responses. Notably, LINC01564 was overexpressed in HNSCC, associated with poorer prognosis, enhanced xenobiotic metabolism, and altered immune cell infiltration. Experimental validation confirmed LINC01564’s role in promoting tumor cell proliferation, invasion, and migration, highlighting its therapeutic potential. Conclusions. Our study highlights the importance of exosome-associated lncRNAs in HNSCC, identifying 17 critical lncRNAs as vital prognostic markers. The upregulation of LINC01564, associated with poor outcomes and increased tumor aggressiveness, underscores its potential as a therapeutic target.