PARD6G mediates resistance to PD-1 immune checkpoint blockade in head and neck squamous cell carcinoma.

Head and neck squamous cell carcinoma (HNSCC) remains a challenging malignancy with limited response to immune checkpoint blockade (ICB) therapies. Identifying reliable biomarkers to predict ICB response is critical for improving clinical outcomes. In this study, we identified PARD6G as a key gene associated with response to anti-PD-1 therapy in HNSCC through integrative analysis of single-cell and bulk transcriptomic data from pre- and post-treatment cohorts. Virtual PARD6G knockout modeling revealed that low PARD6G expression was associated with increased overall immune cell infiltration but significantly reduced infiltration of functional T cells. In vitro, PARD6G overexpression suppressed HNSCC cell proliferation and cell-cycle progression, while its knockdown promoted tumor growth. In vivo, PARD6G-deficient tumors exhibited accelerated growth and resistance to anti-PD-1 treatment, accompanied by a reshaped immune landscape favoring immunosuppression. In conclusion, this study establishes PARD6G as a novel predictive biomarker for anti-PD-1 efficacy and a functional tumor suppressor in HNSCC. Its loss mediates ICB resistance by reshaping the immune microenvironment, providing new insights into the mechanisms of ICB resistance in HNSCC and suggesting potential therapeutic targets.