mRNA-LNP vaccination orchestrates systemic immunity to control human papillomavirus-positive head and neck squamous cell carcinoma.

Messenger RNA (mRNA) vaccines have demonstrated significant potential in cancer immunotherapy by activating both innate and adaptive immunity. However, the detailed cellular and molecular dynamics underpinning these systemic immune responses remain incompletely understood. In this study, we characterized the systemic immune landscape following human papillomavirus (HPV)-targeted mRNA-lipid nanoparticle (LNP) vaccination using single-cell RNA sequencing (scRNA-seq) in a murine model of HPV-positive head and neck squamous cell carcinoma (HNSCC). Our study revealed a coordinated remodeling of the systemic immune landscape, involving the tumor microenvironment (TME), tumor-draining lymph nodes (TDLNs), spleen, and blood. Notably, we pioneered a distinct interferon-stimulated gene (ISG) signature across multiple lymphoid subsets in TDLNs, driven by the LNP component, which contributed to rapid, non-antigen-specific immune activation. Additionally, HPV mRNA-LNP vaccination induced an antigen-specific cycling burst of immune cells that mediated tumor control through a systemic coordination of multi-directional differentiation into anti-tumor cell compositions. These findings enhance our understanding of how mRNA-LNP vaccination orchestrates systemic anti-tumor responses and highlight the therapeutic potential of targeting ISG-expressing and cycling immune cells to improve vaccine efficacy, paving the way for future clinical applications in HPV-related cancers.