Type I interferon restricts mRNA vaccine efficacy through suppression of antigen uptake in cDCs.

Type I interferons (IFN) are key mediators of innate immune activation, promoting upregulation of costimulatory molecules and Major Histocompatibility Complex (MHC) I/II on antigen-presenting cells (APCs). However, IFN also suppress endogenous translation to restrict viral replication. Critically, IFN-stimulated APCs lose the capacity to acquire new antigens, making the timing of IFN signaling a crucial determinant of vaccine efficacy. Here, we show that both DC-specific loss of IFNα/β receptor (IFNαR) and transient blockade of IFNαR before vaccination enhances vaccine uptake and expression within DCs, improves CD8⁺ T cell priming, and leads to superior tumor control. We also demonstrate that IFN signaling before vaccination, triggered by prior infection or administration of a different vaccine, impairs dendritic cell uptake of mRNA-LNP vaccines and reduces the magnitude of vaccine-specific CD8⁺ T cell responses. These findings highlight the dual-edged nature of IFN signaling and offer a potential strategy for enhancing vaccine-induced immunity.