Clinical studies specifically focus on HPV-negative patients due to the presence of overactive CDK4/6-Rb pathway; in contrast, HPV-positive HNSCC is characterized by the viral oncoprotein E7, which degrades Rb protein, so the upstream CDK4/6 pathway rendered redundant, making HPV-positive patients resistant to CDK4/6 inhibitors[49]. Here, RB1 is linked to head and neck squamous cell carcinoma.