Abstract
Most patients with head and neck squamous cell carcinoma (HNSCC) present with locally advanced disease at the time of diagnosis. Current standard treatment strategies mainly include surgery-based multimodal therapy or concurrent chemoradiotherapy. However, existing treatment approaches remain insufficient to meet the therapeutic needs of patients with locally advanced HNSCC. Surgical resection often requires extensive removal of tissues, resulting in functional impairment and substantial deterioration in quality of life. Although concurrent chemoradiotherapy is widely used, patients still face a high risk of early recurrence. The addition of induction chemotherapy may reduce organ dysfunction, but it has not demonstrated a clear improvement in long-term survival and is associated with considerable treatment-related toxicity. In recent years, immunotherapy has shown promising efficacy across multiple malignancies and has reshaped treatment paradigms in certain tumor types. Nevertheless, its application in HNSCC has largely been limited to patients with recurrent or metastatic disease. Based on the theoretical rationale for combining immunotherapy with radiotherapy and chemotherapy, increasing attention has been directed toward advancing the timing of immunotherapy to the neoadjuvant setting. Early integration of immunotherapy may help overcome immunosuppressive barriers, modulate the tumor immune microenvironment, induce durable antitumor immunity, and remodel the immune landscape, thereby promoting tumor regression. This approach has the potential to achieve tumor downstaging, increase resectability, preserve organ function, and improve patients' quality of life. This review summarizes and analyzes the biological mechanisms, current clinical evidence, and existing limitations of neoadjuvant immunotherapy in patients with HNSCC, with the aim of providing safer and more effective treatment options for locally advanced disease. Future perspectives on the development and optimization of neoadjuvant immunotherapy strategies in HNSCC are also discussed.