mRNA-LNP Vaccination Orchestrates Systemic Immunity to Control Human Papillomavirus-positive Oropharyngeal 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. Here, we characterized the systemic immune landscape following human papillomavirus (HPV)-targeted mRNA-lipid nanoparticle (LNP) vaccination using single-cell RNA sequencing (scRNA-seq). Corresponding to vaccination-mediated anti-tumor efficacy in a murine model of HPV-positive oropharyngeal carcinoma (OPSCC), our study revealed evidence for a sophisticated yet coordinated remodeling pattern of systemic immune landscape, involving the tumor microenvironment (TME), tumor-draining lymph nodes (TDLNs), spleen, and blood. Notably, we identified 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 mediate 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.