Tumour-derived exosomes (T-EXOs) impede immune checkpoint blockade therapies, motivating pharmacological efforts to inhibit them. Inspired by how antiviral curvature-sensing peptides disrupt membrane-enveloped virus particles in the exosome size range, we devised a broadly useful strategy that repurposes an engineered antiviral peptide to disrupt membrane-enveloped T-EXOs for synergistic cancer immunotherapy. The membrane-targeting peptide inhibits T-EXOs from various cancer types and exhibits pH-enhanced membrane disruption relevant to the tumour microenvironment. The combination of T-EXO-disrupting peptide and programmed cell death protein-1 antibody-based immune checkpoint blockade therapy improves treatment outcomes in tumour-bearing mice. Peptide-mediated disruption of T-EXOs not only reduces levels of circulating exosomal programmed death-ligand 1, but also restores CD8+ T cell effector function, prevents premetastatic niche formation and reshapes the tumour microenvironment in vivo. Our findings demonstrate that peptide-induced T-EXO depletion can enhance cancer immunotherapy and support the potential of peptide engineering for exosome-targeting applications.
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The data that support the results of this study are available within the paper and its Supplementary Information files. Additional data and files are available from the corresponding authors on reasonable request. Source data are provided with this paper.
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This work was supported by National Research Foundation of Korea grants funded by the Korean government (nos. 2020R1C1C1004385 to J.A.J. and 2021R1A4A1032782 to J.A.J. and J.H.P.); by the Korea Drug Development Fund funded by the Ministry of Science and ICT, Ministry of Trade, Industry and Energy and Ministry of Health and Welfare (no. HN22C0624000022 to J.A.J. and J.H.P.); and by the Brain Pool Program through the National Research Foundation of Korea funded by the Ministry of Science and ICT (no. 2019H1D3A1A01070318 to J.A.J.). In addition, this research was supported by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute funded by the Ministry of Health & Welfare, Republic of Korea (no. HI20C0437020020 to J.H.P.). This research was also supported by a Korean Fund for Regenerative Medicine grant funded by the Korean government (Ministry of Science and ICT, the Ministry of Health and Welfare; no. 21A0503L1 to J.H.P.) and by the SKKU Global Research Platform Research Fund, Sungkyunkwan University, 2022 to J.A.J. Figs. 1a and 2a created with BioRender.com.
J.A.J. is a co-inventor on US patent no. 10,351,604, and S.S., H.K., C.H.K., B.K.Y., S.S., J.A.J. and J.H.P. are named as inventors on US patent application no. 17/818,874 filed by the Sungkyunkwan University Research & Business Foundation. The remaining authors declare no competing interests.
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Shin, S., Ko, H., Kim, C.H. et al. Curvature-sensing peptide inhibits tumour-derived exosomes for enhanced cancer immunotherapy. Nat. Mater. 22, 656–665 (2023). https://doi.org/10.1038/s41563-023-01515-2
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