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Curvature-sensing peptide inhibits tumour-derived exosomes for enhanced cancer immunotherapy

Nature Materials volume 22, pages 656–665 (2023)Cite this article

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Abstract

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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Fig. 1: Repurposed antiviral AH-D peptide disrupts T-EXOs with enhanced activity under tumour pH conditions.
Fig. 2: AH-D peptide prevents T-EXO-mediated CD8+ T cell dysfunction in vitro.
Fig. 3: AH-D peptide enhances aPD-1 antibody therapy and reshapes the TME.
Fig. 4: Combination therapy increases intratumoural CD8+ T cell infiltration and stimulates antitumour immune responses.
Fig. 5: T-EXO disruption inhibits premetastatic niche formation and prevents pulmonary metastasis.

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Data availability

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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Acknowledgements

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.

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  1. These authors contributed equally: Sol Shin, Hyewon Ko.

Authors and Affiliations

  1. Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, Republic of Korea

    Sol Shin, Jeongjin Lee & Jae Hyung Park

  2. Bionanotechnology Research Center, Korea Research Institute of Bioscience & Biotechnology, Daejeon, Republic of Korea

    Hyewon Ko

  3. School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea

    Hyewon Ko

  4. School of Chemical Engineering, College of Engineering, Sungkyunkwan University, Suwon, Republic of Korea

    Chan Ho Kim, Bo Kyeong Yoon, Soyoung Son, Jae Ah Lee, Seok Ho Song, Joshua A. Jackman & Jae Hyung Park

  5. Translational Nanobioscience Research Center, Sungkyunkwan University, Suwon, Republic of Korea

    Bo Kyeong Yoon & Joshua A. Jackman

  6. Biomedical Institute for Convergence at SKKU, Sungkyunkwan University, Suwon, Republic of Korea

    Bo Kyeong Yoon, Joshua A. Jackman & Jae Hyung Park

  7. School of Healthcare and Biomedical Engineering, Chonnam National University, Yeosu, Republic of Korea

    Bo Kyeong Yoon

  8. Division of Biotechnology, Convergence Research Institute, DGIST, Daegu, Republic of Korea

    Jung Min Shin

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Contributions

S.S., H.K., B.K.Y., J.A.J. and J.H.P. planned the studies. S.S., H.K., C.H.K., B.K.Y., S.S., J.A.L., J.M.S., J.L. and S.H.S. conducted experiments. S.S., H.K., C.H.K., B.K.Y., S.S., J.A.L., J.M.S., J.L. and S.H.S. interpreted the results. S.S., H.K., B.K.Y., J.A.J. and J.H.P. wrote the first draft of the paper. J.A.J. and J.H.P. obtained funding. All authors reviewed, edited and approved the paper.

Corresponding authors

Correspondence to Joshua A. Jackman or Jae Hyung Park.

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Competing interests

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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Nature Materials thanks Miguel Castanho, Wei Guo and Michael Mitchell for their contribution to the peer review of this work.

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Supplementary methods, note, Figs. 1–42, references and Tables 1–8.

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Statistical source data for Fig. 5c.

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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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