Navigating resistance to immunotherapy in head-and-neck cancers: Mechanism and novel approaches

Despite the transformative role of immune checkpoint inhibitors (ICIs) in the treatment of head-and-neck squamous cell carcinoma (HNSCC), the majority of patients either fail to respond or eventually relapse due to complex mechanisms of resistance. The inherent and extrinsic factors influencing ICI resistance in HNSCC are examined in this thorough review. Activation of oncogenic pathways, including PI3K and WNT/β-catenin, a high tumor mutational burden with loss of neoantigen expression, and poor antigen presentation are examples of intrinsic processes. Extrinsic processes include the immunosuppressive tumor microenvironment (TME), which is comprised of tumor-associated macrophages, myeloid-derived suppressor cells, regulatory T-cells (T-regs), and the overexpression of other immune checkpoints such as TIM-3, TIGIT, and LAG-3. The review also discusses emerging strategies to overcome resistance, including the combination of ICIs with radiotherapy, targeted therapies, oncolytic viruses, cancer vaccines, toll-like receptor agonists, and nanotechnology-based delivery systems. In addition, precision medicine approaches – leveraging multi-omic profiling and patient-derived organoid models – offer promise for individualized immunotherapy. Novel cellular therapies, such as chimeric antigen receptor-T cells engineered to resist the immunosuppressive TME, are under investigation. Together, these advancements aim to reinvigorate antitumor immunity and expand the clinical benefit of immunotherapy in HNSCC.