biostudies-literatureLobb TANIDA NIH HHSNIAID NIH HHSNHLBI NIH HHSORFDO NIH HHS41https://www.ebi.ac.uk/biostudies/studies/S-EPMC12873219biostudies-literatureUnknown11(1)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 vaNPJ vaccinesType I interferon restricts mRNA vaccine efficacy through suppression of antigen uptake in cDCs.PMC1287321975N99020D0000575N95020D0000575N93022D0000575N92020D0000575N93023D00005DiPaolo RJFerris STDickson ACarrero JAGuo WDalben YAlspach ETse LVLobb TABeeram SfalseType 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 va2026-01-01T00:00:00Z2026 Jan2026-07-15T13:33:27.77Z2026-07-05T03:08:22.022ZS-EPMC128732194148628510.1038/s41541-025-01362-z