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

Gu, W.; Li, R.; Goodrich, H.; Artzi, D.; Cai, S.; Shi, A.; Tsai, Y.-C.; Qin, G.; Li, A.; Goldwasser, E.; Elkasri, N.; Luozhong, S.; Kamada, S.; Wu, Y.; Upadhayay, V.; Zhao, Y.; Yang, Y.; Lau, J.; Sultan, E.; Wirganowicz, A.; Cai, C.; Yu, Q.; Jiang, S.

doi:10.1101/2025.11.23.690059

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bioRxiv · 10.1101/2025.11.23.690059

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

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Abstract

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. HighlightsO_LIArc+ VLVs intensify and extend DC antigen presentation in vivo C_LIO_LIArc+ VLVs directly engage T cells and trigger viral-mimic adjuvanticity C_LIO_LIArc-/- DEVs fail to prime antigen-specific T cell responses C_LIO_LIEngineered Arc+ VLVs drive durable CD8-biased memory and tumor control C_LIO_LIArc+ VLV vaccination provides long-range and cross-tumor protection in vivo C_LI

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Gu, W., Li, R., Goodrich, H., Artzi, D., Cai, S., Shi, A., Tsai, Y.-C., Qin, G., Li, A., Goldwasser, E., Elkasri, N., Luozhong, S., Kamada, S., Wu, Y., Upadhayay, V., Zhao, Y., Yang, Y., Lau, J., Sultan, E., Wirganowicz, A., Cai, C., Yu, Q., Jiang, S.. 2025-11-26. Repurposed endogenous virus-like vesicles mediate dendritic cell long-range antigen presentation and T cell activation for enhanced cancer vaccination. https://doi.org/10.1101/2025.11.23.690059

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