Abstract: Head and neck squamous cell carcinoma (HNSCC) is a tumor characterized by a high degree of immune deficiency and poor prognosis. Its complex immune evasion mechanisms are primarily related to T cell dysfunction and the suppression of anti-tumor immune responses. Immunotherapy aims to modulate the patient’s immune system to recognize and eliminate tumor cells, thereby achieving therapeutic goals. Studies have demonstrated that the tumor microenvironment (TME) plays a pivotal role in HNSCC pathogenesis, facilitating tumorigenesis, progression, and therapy resistance, ultimately contributing to adverse clinical outcomes. Advances in technology have deepened our understanding of the TME, paving the way for novel therapeutic interventions in HNSCC. This review comprehensively summarizes the efficacy and safety of TME-targeted immunotherapies, integrating evidence from published clinical trials, while proposing insights for future research to develop more effective therapeutic strategies.