By combining multi-algorithm machine learning with single-cell and spatial transcriptomics, as well as protein-level experiments, we have not only robustly identified SASH1 as a important biomarker for HNSCC but also systematically elucidated its intrinsic mechanism as a tumor suppressor and its extrinsic potential in regulating the tumor microenvironment. The gene discussed is SASH1; the disease is neoplasm.