Metformin in HPV+ and HPV− HNSCC found a significantly higher increase in apoptosis in HPV−, tobacco‐associated HNSCC (mean 13.7/high power field) compared to HPV+ oropharyngeal squamous cell carcinoma (mean 5.7/high power field, p < 0.001). Additionally, metformin treatment led to an increase in CD8+ T cell infiltrate (22.8% vs. 10.7%, p = 0.006) and FoxP3+ regulatory T cell infiltrate (9% vs. 5%, p = 0.019) in the tumor microenvironment. This evidence concerns the gene FOXP3 and head and neck squamous cell carcinoma.