Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide, characterized by high aggressiveness and frequent metastasis to regional lymph nodes. Despite advances in therapy, including checkpoint inhibitor immunotherapy, surgery, radiotherapy, and chemotherapy, survival rates for patients with advanced HNSCC remain unsatisfactory. This article presents the latest research on predictive biomarkers such as PD-L1, PD-1, CTLA-4, p53, and HPV, which may enhance treatment efficacy and improve clinical outcomes for patients. The clinical value of these biomarkers, their limitations, and their potential application in HNSCC therapy are emphasized. Special attention is given to immunotherapy, which shows promising results in treating this type of cancer through the modulation of the immune response. The review’s findings highlight the need for further research on new biomarkers to develop more personalized and effective therapeutic strategies for HNSCC patients.