TY  - EJOU
AU  - Hussain, Abbas 
AU  - Jones, Daniel Thomas 
AU  - Nanda, Rishi Kumar 
AU  - Srinivasmurthy, Ramaditya 
AU  - Ta, Jason 
AU  - Myat, Yin Mon 
AU  - Hattin, Riccesha 
AU  - Bigcas, Jo-Lawrence 
AU  - Tian, Sisi 
AU  - Shah, Suparna 
AU  - Wang, Robert 
AU  - Thein, Kyaw Zin 

TI  - Resistance Mechanisms in Immunotherapy-Radiotherapy/Chemotherapy Combinations in Locally Advanced Head \& Neck Squamous Cell Carcinoma
T2  - Oncology Research

PY  - 
VL  - 
IS  - 
SN  - 1555-3906

AB  - 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.
KW  - 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)

DO  - 10.32604/or.2026.077918