Journal Article Review Epublish
PubMed: 40547025 DOI: 10.3389/fimmu.2025.1596583
Advances and challenges in immunotherapy in head and neck cancer.
Front Immunol 16:1596583
Authors: Hazem Aboaid, Taimur Khalid, Abbas Hussain, Yin Mon Myat, Rishi Kumar Nanda, Ramaditya Srinivasmurthy, Kevin Nguyen, Daniel Thomas Jones, Jo-Lawrence Bigcas, Kyaw Zin Thein
Affiliations
- Department of Internal Medicine, Kirk Kerkorian School of Medicine at University of Nevada, Las Vegas (UNLV), Las Vegas, NV, United States.
- Kirk Kerkorian School of Medicine at University of Nevada, Las Vegas (UNLV), Las Vegas, NV, United States.
- Department of Internal Medicine, One Brooklyn Health-Interfaith Medical Center, Brooklyn, NY, United States.
- Touro University Nevada College of Osteopathic Medicine, Las Vegas, NV, United States.
- Department of Otolaryngology - Head and Neck Surgery, Kirk Kerkorian School of Medicine at University of Nevada, Las Vegas, Las Vegas, NV, United States.
- Division of Hematology and Medical Oncology, Comprehensive Cancer Centers of Nevada, Las Vegas, NV, United States.
Abstract
Head and neck squamous cell carcinoma (HNSCC) remains a challenging malignancy with suboptimal survival outcomes despite advances in surgery, radiotherapy, and chemotherapy. Immunotherapy, particularly immune checkpoint inhibitors (ICIs) targeting programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1), has transformed treatment paradigms, yet its full potential in HNSCC is still being explored. This review evaluates the current landscape of immunotherapy in both locally advanced (LA) and recurrent/metastatic (R/M) HNSCC, discussing key clinical trials, emerging biomarkers, and novel therapeutic strategies. For LA HNSCC, phase III trials such as KEYNOTE-412 and JAVELIN Head and Neck 100 failed to demonstrate survival benefits with ICI-chemoradiotherapy combinations in unselected populations, though post hoc analyses suggest efficacy in PD-L1-positive tumors. Recent studies, including KEYNOTE-689 and NIVOPOSTOP GORTEC 2018-01, indicate potential benefits of perioperative ICIs in resectable disease. In R/M HNSCC, ICIs have redefined the standard of care. KEYNOTE-040 and CheckMate 141 led to Food and Drug Administration (FDA) approvals of pembrolizumab and nivolumab, while KEYNOTE-048 established pembrolizumab monotherapy for PD-L1 combined positive score (CPS) ≥1 and pembrolizumab plus chemotherapy as first-line treatment. However, dual checkpoint blockade trials (KESTREL, CheckMate 651) have yielded mixed results, highlighting the complexity of immune resistance. Beyond ICIs, emerging strategies include oncolytic virotherapy, chimeric antigen receptor-T cell therapy (CAR-T), and cancer vaccines, with promising preclinical and early-phase clinical results. Biomarkers such as PD-L1 expression, tumor mutational burden (TMB), and Human Papillomavirus (HPV) status play a critical role in treatment selection, but further validation is needed. Despite advancements, challenges persist, including heterogeneous response rates, immune-related toxicities, and optimal integration of immunotherapy in multimodal treatment regimens. Future research should focus on refining biomarker-driven treatment algorithms, developing rational immunotherapy combinations, and leveraging tumor microenvironment modifications to enhance therapeutic efficacy.
MeSH
Radiotherapy, Cells, Neoplasms, Drug Therapy, Biomarkers, Immunotherapy, Immune Checkpoint Inhibitors, Squamous Cell Carcinoma Of Head And Neck, Immune System Diseases, Chemoradiotherapy, Head And Neck Neoplasms, Therapeutics, Alphapapillomavirus, Cell Death, Receptors, Antigen, T-Cell, Chemotherapy, Human Papillomavirus Viruses