Thus, development of new strategies to improve therapeutic outcome of patients with HPV(−) HNSCC using our mechanistic data might have significant impact to improve chemotherapy‐mediated tumor suppression by at least in part inducing E2F5‐Drp1‐ceramide‐dependent lethal mitophagy without the oncogenic HPV infection. The gene discussed is E2F5; the disease is head and neck squamous cell carcinoma.