Immunotherapy for oral cavity tumors: recent advances, key challenges, and future perspectives

Oral cavity tumors remain a major global health challenge, with poor outcomes in patients with locally advanced, recurrent, or metastatic disease despite advances in surgery, radiotherapy, chemotherapy, and targeted therapies. Immunotherapy has emerged as a potential strategy to restore antitumor immunity and overcome tumor-induced immune suppression. This narrative review synthesizes recent advances in immunotherapy for oral cavity tumors, focusing on immune checkpoint inhibitors (ICIs), tyrosine kinase inhibitor (TKI) antibodies, near-infrared photoimmunotherapy (NIR-PIT), bispecific antibodies (BsAbs), oncolytic viruses (OVs), cytokine therapies, and adoptive cell therapies such as tumor-infiltrating lymphocyte (TIL) therapy, chimeric antigen receptor (CAR)-T/natural killer (NK), and T cell receptor (TCR)-T therapy. The review also examines the pivotal role of the immunosuppressive tumor microenvironment (TME) in shaping treatment response and therapeutic resistance, highlighting the contributions of regulatory immune cells, cancer-associated fibroblasts (CAFs), hypoxia, extracellular matrix (ECM) remodeling, and immune exclusion. Current clinical evidence demonstrates meaningful survival benefits with programmed cell death protein 1 (PD-1) inhibitors in recurrent/metastatic disease and expanding opportunities for perioperative immunotherapy, while numerous emerging modalities remain under active clinical investigation. However, durable responses remain limited by tumor heterogeneity, inadequate immune cell trafficking, antigen escape, manufacturing challenges, and the lack of reliable predictive biomarkers. Future progress will likely depend on biomarker-guided patient selection, rational combination strategies, and engineered cellular therapies that can overcome microenvironment-mediated resistance. Collectively, these findings support continued investigation of personalized, multimodal immunotherapy as a viable avenue for improving outcomes in patients with oral squamous cell carcinoma (OSCC).