Single-Cell Analysis Identifies an LDL Metabolism–Driven Myeloid Signature and ITGA5-Associated Progression in HNSCC

Background: Lipid metabolic reprogramming is a hallmark of tumor progression, yet the role of low-density lipoprotein (LDL) metabolism in head and neck squamous cell carcinoma (HNSCC) remains unclear. This study aimed to systematically characterize LDL metabolism and identify clinically relevant regulators. Methods: Integrated multi-omics analyses were performed using TCGA and GEO cohorts. Single-cell RNA sequencing was applied to resolve cell-type–specific metabolic heterogeneity. A machine learning–based prognostic model was developed and validated across independent datasets. Functional analyses, immune profiling, and tumor mutation analyses were conducted. Key genes were further validated using spatial transcriptomics and in vitro experiments. Results: LDL metabolic activity exhibited marked heterogeneity, with myeloid cells—particularly macrophages—showing the highest activity. The LDL-related prognostic model effectively stratified patients by survival and immunotherapy response. High-risk patients displayed elevated tumor mutational burden, reduced immune infiltration, and poorer response to immune checkpoint blockade. Notably, the macro_SPP1 macrophage subset exhibited enhanced LDL metabolism and extracellular matrix activity, along with upregulated ITGA5. Integrated analyses indicated that ITGA5 is associated with cholesterol metabolism, immune regulation, and macrophage differentiation. Spatial transcriptomics confirmed its enrichment in tumor regions with high LDL activity. Functional experiments demonstrated that ITGA5 promotes proliferation, migration, and invasion of HNSCC cells. Conclusion: LDL metabolic reprogramming shapes the tumor microenvironment and clinical outcomes in HNSCC. ITGA5 acts as a key mediator linking lipid metabolism to malignant progression, representing a potential prognostic biomarker and therapeutic target.