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

Dendritic cells (DCs) can process patient-derived antigens to generate extracellular vesicles (DEVs) vaccines, which can be personalized and rapidly adapted to the evolving antigenic profile in chronic diseases. These DEVs present antigens and stimulate T cell responses, but their clinical efficacy is limited by poorly understood mechanisms. This study reveals how DCs incorporate ancient viral genes to produce endogenous virus-like vesicles (VLVs) that enable long-range T cell communication. Overexpressing a viral capsid protein Arc and a capsid-stabilizer substantially boosted DEVs’ antigen-presentation capabilities and immune responses, whereas Arc-deficient DEVs failed to generate specific immune memory. Proteomic analysis revealed that engineered virus-like vesicles (eraVLVs) enhance antigen presentation on MHC-I, recruit viral proteins for direct T cell interaction, and act as built-in adjuvants to boost broad immune responses. Using a cancer vaccine platform independent of model-specific antigens, we demonstrated robust and broad anti-cancer efficacy, with eraVLVs substantially extending median survival.