This phase 1 clinical trial, designed in patients with recurrent HNSCC undergoing salvage surgery to evaluate the safety of combining chronic PDE5 inhibition to reverse tumor-induced immunosuppression, and MUC1/polyICLC immunization to prime a tumor specific immune response, seems to confirm the previous clinical evidence indicating beneficial actions for these two interventions in patients with malignancies. Here, PDE5A is linked to head and neck squamous cell carcinoma.