Single-Cell Oscc Tme: Yy1/Nts-Driven Immunosuppression

The response rate to immune checkpoint blockade (ICB) therapy in oral squamous cell carcinoma (OSCC) remains below 25%, primarily due to the immunosuppressive tumor microenvironment (TME). This study aims to resolve TME heterogeneity using single-cell multi-omics and elucidate the key molecular mechanisms driving immunosuppressive TME formation. Single-cell transcriptomic data from 83 OSCC patients (112 samples, 400,000 cells) were integrated. Batch effects were removed using the scVI algorithm, tumor cells were identified via InferCNV, and TME subtypes were classified using ConsensusClusterPlus. Survival analysis was conducted using TCGA data, with validation through multiplex immunohistochemistry, flow cytometry, and murine orthotopic models. OSCC-TME was classified into six subtypes at single-cell resolution for the first time: tertiary lymphoid, immune-activated, MDSC-enriched, immune-resident, stroma-enriched, and tumor-enriched. A tumor cell subpopulation (TFM5) uniquely enriched in high-risk TME was identified. Its core transcription factor YY1 expression linked to poor OSCC prognosis .Mechanistic studies revealed that YY1 transcriptionally regulates neurotensin (NTS), inducing mast cell degranulation, MDSC expansion, and Treg recruitment. Murine models confirmed that YY1 knockdown enhanced αPD1 efficacy. This study systematically maps the OSCC immune microenvironment and uncovers a novel YY1/NTS axis-driven mechanism of immune suppression via mast cell activation. The findings provide a theoretical basis for targeting tumor cell-intrinsic pathways to remodel TME and improve ICB efficacy.