Head and neck cancer (HNC) remains a significant global health burden, with high morbidity and mortality despite advances in conventional therapies. The immunosuppressive tumor microenvironment (TME) and tumor heterogeneity have limited the efficacy of current treatments, driving the exploration of novel immunotherapeutic strategies. Immune checkpoint inhibitors (ICIs) have established a role in recurrent/metastatic HNC, yet response rates remain modest and resistance is common. In this context, mRNA vaccines have emerged as a transformative approach due to their flexibility, rapid development, and ability to induce potent, antigen-specific immune responses. This review provides a comprehensive analysis of the application of mRNA vaccines in HNC immunotherapy, focusing on three major antigen sources: tumor-associated antigens (TAAs), tumor-specific neoantigens (TSAs), and virus-associated antigens such as HPV E6/E7. We examine the advantages and limitations of different delivery platforms-including lipid nanoparticles (LNPs), self-amplifying RNA (saRNA), and ex vivo dendritic cell (DC)-mRNA vaccines-and discuss their integration with other modalities such as ICIs, chemotherapy, and radiation therapy. Preclinical and clinical data demonstrate that personalized neoantigen vaccines can elicit robust T-cell responses and improve survival outcomes, particularly in HPV-positive HNSCC. However, challenges such as tumor heterogeneity, inefficient delivery, immunosuppressive TME, manufacturing complexity, and lack of predictive biomarkers hinder widespread translation. Future directions include the development of "off-the-shelf" shared-antigen vaccines, next-generation delivery systems with enhanced targeting, combination regimens, and biomarker-guided patient selection. With continued innovation in mRNA technology and translational research, mRNA vaccines hold immense potential to redefine the treatment paradigm for HNC, offering durable immune protection and improved clinical outcomes.
