Repurposed endogenous virus-like vesicles mediate dendritic cell long-range antigen presentation and T cell activation for enhanced cancer vaccination

Summary Dendritic cells (DCs) release extracellular vesicles (DEVs) that amplify antigen presentation while incorporating patient-derived, rapidly evolving antigens. By enriching peptide-MHC and co-stimulatory ligands orders-of-magnitude above donor-cell levels, DEVs emerge as potent vesicle-vaccines, although efficacy remains limited by unclear mechanisms. We show that DCs repurpose viral components to generate endogenous virus-like vesicles (VLVs) that preferentially carry peptide-MHC and high-density co-stimulatory ligands, intensifying and extending antigen presentation. Upon antigen exposure, Arc partners with endogenous envelope proteins to assemble VLVs that directly engage T cells and trigger intrinsic adjuvanticity via viral mimicry. Arc⁻/⁻ DEVs failed to prime antigen-specific T cell responses, whereas Arc overexpression with its 5′-UTR stem-loop shifted DEVs toward VLVs that trafficked to lymphoid organs, drove rapid CD4-assisted priming and durable CD8-biased memory, suppressed melanoma, and prolonged survival. These reveal a viral-mimicry mechanism enabling long-range immune activation and support Arc + VLVs as an antigen-agnostic vaccine for cancer immunotherapy. Highlights Arc + VLVs intensify and extend DC antigen presentation in vivo Arc + VLVs directly engage T cells and trigger viral-mimic adjuvanticity Arc ⁻/⁻ DEVs fail to prime antigen-specific T cell responses Engineered Arc + VLVs drive durable CD8-biased memory and tumor control Arc + VLV vaccination provides long-range and cross-tumor protection in vivo