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REVIEW

Resistance Mechanisms in Immunotherapy-Radiotherapy/Chemotherapy Combinations in Locally Advanced Head & Neck Squamous Cell Carcinoma

Abbas Hussain1,*, Daniel Thomas Jones2, Rishi Kumar Nanda3, Ramaditya Srinivasmurthy4, Jason Ta5, Yin Mon Myat6, Riccesha Hattin1, Jo-Lawrence Bigcas7, Sisi Tian7, Suparna Shah7, Robert Wang7, Kyaw Zin Thein8
1 Department of Internal Medicine, Kirk Kerkorian School of Medicine at UNLV, Las Vegas, NV, USA
2 Department of Internal Medicine, Sunrise Health GME Consortium, Las Vegas, NV, USA
3 College of Osteopathic Medicine, Touro University Nevada, Las Vegas, NV, USA
4 Department of Internal Medicine, Mount Sinai Morningside/West, Mount Sinai, New York, NY, USA
5 Department of Internal Medicine, HCA Healthcare/USF Morsani College of Medicine GME: HCA Florida Citrus Hospital, Inverness, FL, USA
6 Department of Internal Medicine, One Brooklyn Health: Interfaith Medical Center Campus, Brooklyn, NY, USA
7 Department of Otolaryngology-Head & Neck Surgery, University of Nevada, Las Vegas, NV, USA
8 Division of Hematology and Medical Oncology, Comprehensive Cancer Centers of Nevada, Las Vegas, NV, USA
* Corresponding Author: Abbas Hussain. Email: email
(This article belongs to the Special Issue: New Insights in Drug Resistance of Cancer Therapy: A New Wine in an Old Bottle)

Oncology Research https://doi.org/10.32604/or.2026.077918

Received 19 December 2025; Accepted 21 April 2026; Published online 19 May 2026

Abstract

Locally advanced head and neck squamous cell carcinoma (LA-HNSCC) remains difficult to treat despite multimodal therapy. Immune checkpoint inhibitors (ICIs) have expanded treatment options, but phase III trials combining ICIs with chemoradiotherapy have demonstrated limited survival benefit due to complex resistance mechanisms. These include immunosuppressive tumor microenvironments, impaired DNA damage responses, hypoxia-driven adaptations, metabolic reprogramming, and oncogenic signaling via the HER receptor family. This review outlines key resistance pathways and emerging strategies to overcome them. Nanotechnology-based approaches may enhance drug delivery and modulate the tumor microenvironment, while dual inhibition of epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 3 (HER3), and downstream pathways shows promise in addressing compensatory signaling. Advances in biomarkers, including programmed death-ligand 1 (PD-L1), circulating tumor DNA, metabolic profiling, and radiomics, enable improved patient selection and monitoring. Novel immune checkpoints and adoptive cellular therapies, alongside personalized and adaptive trial designs, offer potential to improve outcomes in LA-HNSCC.

Keywords

Locally advanced head and neck squamous cell carcinoma (LA-HNSCC); combination immunotherapy strategies; radiosensitization and immunotherapy; immunotherapy resistance; precision immuno-oncology; translational oncology; tumor microenvironment (TME)

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