Oncolytic viruses in head and neck cancer: therapeutic promise and translational challenges

Head and neck squamous cell carcinoma (HNSCC) remains difficult to treat, particularly in patients with HPV-negative disease. These patients often get diagnosed too late, their cancer doesn't respond well to treatment, and they don't live as long. Oncolytic viruses (OVs) can be used for treating cancer instead of using other cytotoxic methods since they can kill malignant cells directly and cause both local and systemic anti-cancer immune responses. In this review, we focus on current evidence of oncolytic virotherapy (OVT) in HNSCC, including that OVs selectively infect tumor cells, induce tumor cell lysis and immunogenic cell death, and modulate the tumor microenvironment. We also compare some OV platforms which were studied in HNSCC or similar solid-tumor settings: Herpes simplex virus (HSV), adenovirus, vaccinia virus, reovirus, measles virus, vesicular stomatitis virus, and Newcastle disease virus. Finally, we discuss emerging strategies to improve the efficacy and clinical translation of OVT for HNSCC, including tumor- or stimulus-responsive promoters, engineering of viral tropism and receptor specificity, modulation of both antiviral and immunosuppressive pathways, and incorporation between therapeutic payloads and advanced delivery systems. Altogether these developments support further exploration of OVs within biomarker-informed multimodal therapy for select patients of HNSCC.