PARD6G mediates resistance to PD-1 immune checkpoint blockade in head and neck squamous cell carcinoma
- Int Immunopharmacol. 2026 Sep 1:184:116949. doi: 10.1016/j.intimp.2026.116949.
- 1. School of Medical Technology and Information Engineering, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, China; Laboratory Medicine Center, Allergy Center, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou, Zhejiang 310014, People's Republic of China; Key Laboratory of Precision Medicine for Head and Neck Cancers of Zhejiang Province, Zhejiang Provincial People's Hospital, Hangzhou, Zhejiang 310014, China.
- 2. School of Medical Technology and Information Engineering, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, China; Laboratory Medicine Center, Allergy Center, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou, Zhejiang 310014, People's Republic of China.
- 3. Clinical Laboratory, The Third Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310014, China.
- 4. Laboratory Medicine Center, Allergy Center, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou, Zhejiang 310014, People's Republic of China.
- 5. Laboratory Medicine Center, Allergy Center, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou, Zhejiang 310014, People's Republic of China. Electronic address: [email protected].
- 6. Key Laboratory of Precision Medicine for Head and Neck Cancers of Zhejiang Province, Zhejiang Provincial People's Hospital, Hangzhou, Zhejiang 310014, China. Electronic address: [email protected].
- 7. School of Medical Technology and Information Engineering, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, China; Laboratory Medicine Center, Allergy Center, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou, Zhejiang 310014, People's Republic of China; Key Laboratory of Precision Medicine for Head and Neck Cancers of Zhejiang Province, Zhejiang Provincial People's Hospital, Hangzhou, Zhejiang 310014, China; Key Laboratory for Cancer Prevention and treatment of Guizhou Province, Bijie, Guizhou 551700, China; Zhejiang Provincial People's Hospital Bijie Hospital (The First People's Hospital of Bijie), Guizhou 551799, P. R. China. Electronic address: [email protected].
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.