Administration of PDE-5 inhibitors such as sildenafil and tadalafil in mouse models has been shown to reactivate the immune response against tumors through T cells and NK cells, leading to prolonged survival.211 Clinical trials have demonstrated enhanced intratumoral T-cell activity and improved outcomes in patients with head and neck squamous cell carcinoma (HNSCC) and metastatic melanoma.212,213 Additionally, targeting other molecules such as phosphatidylinositol 3-kinase (PI3K), Entinostat, and STAT3 inhibitors can also reverse the immunosuppressive function of MDSCs.214–216. This evidence concerns the gene PDE5A and head and neck squamous cell carcinoma.