Oral squamous cell carcinoma (OSCC) remains a significant global health challenge with high mortality rates, particularly in advanced stages, despite advancements in traditional treatment modalities such as surgery, radiation, and chemotherapy. In recent years, immunotherapy has emerged as a promising strategy by harnessing the body’s immune system to combat OSCC. However, the highly immunosuppressive tumor microenvironment (TME), composed of regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages (TAMs), and immunosuppressive cytokines, promotes immune evasion and tumor progression, limiting the effectiveness of immunotherapeutic interventions.

Immune checkpoint inhibitors (ICIs), targeting molecules such as PD-1/PD-L1 and CTLA-4, have shown potential in restoring T cell activity and improving survival outcomes, with pembrolizumab and nivolumab demonstrating efficacy in recurrent or metastatic OSCC. Nevertheless, variable response rates highlight the need for predictive biomarkers, including PD-L1 expression, tumor mutational burden (TMB), and microsatellite instability (MSI), to enhance patient selection for ICI therapy. Additionally, monoclonal antibodies targeting epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) offer therapeutic benefits when combined with conventional treatments.

Emerging immunotherapeutic strategies, such as cancer vaccines (peptide-based and dendritic cell vaccines) and adoptive cell therapies, including chimeric antigen receptor (CAR)-T cell therapy, show potential in overcoming immune resistance. However, challenges such as immune-related adverse events (irAEs), tumor heterogeneity, and immune escape mechanisms hinder the widespread success of immunotherapy.

Future research must focus on optimizing combination therapies, exploring resistance pathways, and identifying novel immunotherapeutic targets to enhance treatment efficacy and improve patient outcomes. This review underscores the evolving landscape of OSCC immunotherapy, highlighting both current advancements and future directions in the pursuit of more effective and durable treatment strategies.