A multitude of upstream components regulating the PI3K/AKT/mTOR pathway are altered in human cancers18, thus we reasoned that the identification of the mechanisms sustaining PI3K/AKT/mTOR signaling in >80% of HNSCC that do not harbor PIK3CA mutations may provide opportunities for novel combination treatment options with ICB for the majority of patients that do not respond to anti-PD-1 treatment. The gene discussed is PIK3CA; the disease is head and neck squamous cell carcinoma.