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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.