Unraveling resistance to immune checkpoint inhibitors in HNSCC: from mechanisms to combination therapies

Head and neck squamous cell carcinoma (HNSCC), which arises from the mucosal linings of the oral cavity, pharynx, and larynx, represents the most prevalent head and neck malignancy. This cancer is notable for its elevated incidence and substantial mortality. The intricate anatomy of the region contributes to marked tumor heterogeneity, rendering the pursuit of effective therapeutic regimens a crucial aspect of enhancing clinical outcomes. Recently, the advent of immune checkpoint blockade, particularly agents targeting programmed death-1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4, has introduced significant advancements within the oncological landscape, including for HNSCC. The introduction of immune checkpoint inhibitors, specifically the PD-1 blockers pembrolizumab and nivolumab, has established a new therapeutic standard for recurrent/metastatic HNSCC (R/M HNSCC). However, the clinical benefit is not universal, as a primary challenge remains the high incidence of treatment resistance. Consequently, a majority of patients (approximately 60%-70%) with R/M HNSCC derive minimal or no benefit from this form of immunotherapy, highlighting the critical need to understand the underlying resistance mechanisms. This review comprehensively discusses the types of immunotherapy resistance in HNSCC and the underlying mechanisms contributing to resistance. Furthermore, it reviews current strategies to overcome immunotherapy resistance, providing new perspectives for improving therapeutic efficacy in HNSCC.