Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

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

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.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

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.

Similar content being viewed by others

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.

References

  1. Tang, J. et al. The clinical trial landscape for PD1/PDL1 immune checkpoint inhibitors. Nat. Rev. Drug Discov. 17, 854–855 (2018).

    Article  CAS  Google Scholar 

  2. Ribas, A. & Wolchok, J. D. Cancer immunotherapy using checkpoint blockade. Science 359, 1350–1355 (2018).

    Article  CAS  Google Scholar 

  3. Sharma, P., Hu-Lieskovan, S., Wargo, J. A. & Ribas, A. Primary, adaptive, and acquired resistance to cancer immunotherapy. Cell 168, 707–723 (2017).

    Article  CAS  Google Scholar 

  4. Sun, C., Mezzadra, R. & Schumacher, T. N. Regulation and function of the PD-L1 checkpoint. Immunity 48, 434–452 (2018).

    Article  CAS  Google Scholar 

  5. Cha, J.-H., Chan, L.-C., Li, C.-W., Hsu, J. L. & Hung, M.-C. Mechanisms controlling PD-L1 expression in cancer. Mol. Cell 76, 359–370 (2019).

    Article  CAS  Google Scholar 

  6. Daassi, D., Mahoney, K. M. & Freeman, G. J. The importance of exosomal PDL1 in tumour immune evasion. Nat. Rev. Immunol. 20, 209–215 (2020).

    Article  CAS  Google Scholar 

  7. Poggio, M. et al. Suppression of exosomal PD-L1 induces systemic anti-tumor immunity and memory. Cell 177, 414–427 (2019).

    Article  CAS  Google Scholar 

  8. Yang, Y. et al. Exosomal PD-L1 harbors active defense function to suppress T cell killing of breast cancer cells and promote tumor growth. Cell Res. 28, 862–864 (2018).

    Article  CAS  Google Scholar 

  9. Chen, G. et al. Exosomal PD-L1 contributes to immunosuppression and is associated with anti-PD-1 response. Nature 560, 382–386 (2018).

    Article  CAS  Google Scholar 

  10. Zhang, C. et al. Anti-PD-1 therapy response predicted by the combination of exosomal PD-L1 and CD28. Front. Oncol. 10, 760 (2020).

    Article  CAS  Google Scholar 

  11. Del Re, M. et al. Blood-based PD-L1 analysis in tumor-derived extracellular vesicles: applications for optimal use of anti-PD-1/PD-L1 axis inhibitors. Biochim. Biophys. Acta Rev. Cancer 1875, 188463 (2021).

    Article  Google Scholar 

  12. Pegtel, D. M. & Gould, S. J. Exosomes. Annu. Rev. Biochem. 88, 487–514 (2019).

    Article  CAS  Google Scholar 

  13. Marar, C., Starich, B. & Wirtz, D. Extracellular vesicles in immunomodulation and tumor progression. Nat. Immunol. 22, 560–570 (2021).

    Article  CAS  Google Scholar 

  14. Xie, F. et al. Extracellular vesicles in cancer immune microenvironment and cancer immunotherapy. Adv. Sci. 6, 1901779 (2019).

    Article  CAS  Google Scholar 

  15. Zhang, H., Lu, J., Liu, J., Zhang, G. & Lu, A. Advances in the discovery of exosome inhibitors in cancer. J. Enzyme Inhib. Med. Chem. 35, 1322–1330 (2020).

    Article  CAS  Google Scholar 

  16. Kwon, S. et al. Engineering approaches for effective therapeutic applications based on extracellular vesicles. J. Control. Release 330, 15–30 (2021).

    Article  CAS  Google Scholar 

  17. Catalan’, M. & O’Driscoll, L. Inhibiting extracellular vesicles formation and release: a review of EV inhibitors. J. Extracell. Vesicles 9, 1703244 (2020).

    Article  Google Scholar 

  18. Nolte-‘t Hoen, E., Cremer, T., Gallo, R. C. & Margolis, L. B. Extracellular vesicles and viruses: are they close relatives? Proc. Natl Acad. Sci. USA 113, 9155–9161 (2016).

    Article  Google Scholar 

  19. Jackman, J. A. et al. Therapeutic treatment of Zika virus infection using a brain-penetrating antiviral peptide. Nat. Mater. 17, 971–977 (2018).

    Article  CAS  Google Scholar 

  20. Jackman, J. A., Shi, P.-Y. & Cho, N.-J. Targeting the Achilles heel of mosquito-borne viruses for antiviral therapy. ACS Infect. Dis. 5, 4–8 (2019).

    Article  CAS  Google Scholar 

  21. de Lázaro, I. & Mooney, D. J. Obstacles and opportunities in a forward vision for cancer nanomedicine. Nat. Mater. 20, 1469–1479 (2021).

    Article  Google Scholar 

  22. Jackman, J. A., Goh, H. Z., Zhdanov, V. P., Knoll, W. & Cho, N.-J. Deciphering how pore formation causes strain-induced membrane lysis of lipid vesicles. J. Am. Chem. Soc. 138, 1406–1413 (2016).

    Article  CAS  Google Scholar 

  23. Camargos, V. N. et al. In-depth characterization of congenital Zika syndrome in immunocompetent mice: antibody-dependent enhancement and an antiviral peptide therapy. EBioMedicine 44, 516–529 (2019).

    Article  Google Scholar 

  24. Cho, N.-J. et al. Mechanism of an amphipathic α-helical peptide’s antiviral activity involves size-dependent virus particle lysis. ACS Chem. Biol. 4, 1061–1067 (2009).

    Article  CAS  Google Scholar 

  25. Park, S., Jackman, J. A. & Cho, N.-J. Comparing the membrane-interaction profiles of two antiviral peptides: insights into structure–function relationship. Langmuir 35, 9934–9943 (2019).

    Article  CAS  Google Scholar 

  26. Webb, B. A., Chimenti, M., Jacobson, M. P. & Barber, D. L. Dysregulated pH: a perfect storm for cancer progression. Nat. Rev. Cancer 11, 671–677 (2011).

    Article  CAS  Google Scholar 

  27. Jackman, J. A., Zan, G. H., Zhdanov, V. P. & Cho, N.-J. Rupture of lipid vesicles by a broad-spectrum antiviral peptide: influence of vesicle size. J. Phys. Chem. B 117, 16117–16128 (2013).

    Article  CAS  Google Scholar 

  28. Snider, C., Jayasinghe, S., Hristova, K. & White, S. H. MPEx: a tool for exploring membrane proteins. Protein Sci. 18, 2624–2628 (2009).

    Article  CAS  Google Scholar 

  29. Badani, H., Garry, R. F. & Wimley, W. C. Peptide entry inhibitors of enveloped viruses: the importance of interfacial hydrophobicity. Biochim. Biophys. Acta Biomembr. 1838, 2180–2197 (2014).

    Article  CAS  Google Scholar 

  30. Ricklefs, F. L. et al. Immune evasion mediated by PD-L1 on glioblastoma-derived extracellular vesicles. Sci. Adv. 4, eaar2766 (2018).

    Article  Google Scholar 

  31. Shen, D. D. et al. LSD1 deletion decreases exosomal PD-L1 and restores T-cell response in gastric cancer. Mol. Cancer 21, 75 (2022).

    Article  CAS  Google Scholar 

  32. Batlle, E. & Massagué, J. Transforming growth factor-β signaling in immunity and cancer. Immunity 50, 924–940 (2019).

    Article  CAS  Google Scholar 

  33. Guha, S., Ghimire, J., Wu, E. & Wimley, W. C. Mechanistic landscape of membrane-permeabilizing peptides. Chem. Rev. 119, 6040–6085 (2019).

    Article  CAS  Google Scholar 

  34. Furukawa, N. & Popel, A. S. Peptides that immunoactivate the tumor microenvironment. Biochim. Biophys. Acta Rev. Cancer 1875, 188486 (2021).

    Article  CAS  Google Scholar 

  35. Momin, N. et al. Maximizing response to intratumoral immunotherapy in mice by tuning local retention. Nat. Commun. 13, 109 (2022).

    Article  CAS  Google Scholar 

  36. Webber, J., Steadman, R., Mason, M. D., Tabi, Z. & Clayton, A. Cancer exosomes trigger fibroblast to myofibroblast differentiation. Cancer Res. 70, 9621–9630 (2010).

    Article  CAS  Google Scholar 

  37. Chen, X. & Song, E. Turning foes to friends: targeting cancer-associated fibroblasts. Nat. Rev. Drug Discov. 18, 99–115 (2019).

    Article  CAS  Google Scholar 

  38. Merritt, C. R. et al. Multiplex digital spatial profiling of proteins and RNA in fixed tissue. Nat. Biotechnol. 38, 586–599 (2020).

    Article  CAS  Google Scholar 

  39. Hoshino, A. et al. Tumour exosome integrins determine organotropic metastasis. Nature 527, 329–335 (2015).

    Article  CAS  Google Scholar 

  40. Ortiz, A. et al. An interferon-driven oxysterol-based defense against tumor-derived extracellular vesicles. Cancer Cell 35, 33–45 (2019).

    Article  CAS  Google Scholar 

  41. Lu, Z. et al. Regulation of intercellular biomolecule transfer–driven tumor angiogenesis and responses to anticancer therapies. J. Clin. Invest. 131, e144225 (2021).

    Article  CAS  Google Scholar 

  42. Ji, Q. et al. Primary tumors release ITGBL1-rich extracellular vesicles to promote distal metastatic tumor growth through fibroblast-niche formation. Nat. Commun. 11, 1211 (2020).

    Article  CAS  Google Scholar 

  43. Grum-Schwensen, B. et al. Suppression of tumor development and metastasis formation in mice lacking the S100A4(mts1) gene. Cancer Res. 65, 3772–3780 (2005).

    Article  CAS  Google Scholar 

  44. Fang, T. et al. Tumor-derived exosomal miR-1247-3p induces cancer-associated fibroblast activation to foster lung metastasis of liver cancer. Nat. Commun. 9, 191 (2018).

    Article  Google Scholar 

  45. Vitale, I. et al. Targeting cancer heterogeneity with immune responses driven by oncolytic peptides. Trends Cancer 7, 557–572 (2021).

    Article  CAS  Google Scholar 

  46. Rodrigues, G. et al. Tumour exosomal CEMIP protein promotes cancer cell colonization in brain metastasis. Nat. Cell Biol. 21, 1403–1412 (2019).

    Article  CAS  Google Scholar 

  47. Gao, L. et al. Tumor-derived exosomes antagonize innate antiviral immunity. Nat. Immunol. 19, 233–245 (2018).

    Article  CAS  Google Scholar 

  48. Woo, C. H. et al. Small extracellular vesicles from human adipose-derived stem cells attenuate cartilage degeneration. J. Extracell. Vesicles 9, 1735249 (2020).

    Article  CAS  Google Scholar 

  49. Jackman, J. A., Zhao, Z., Zhdanov, V. P., Frank, C. W. & Cho, N.-J. Vesicle adhesion and rupture on silicon oxide: influence of freeze–thaw pretreatment. Langmuir 30, 2152–2160 (2014).

    Article  CAS  Google Scholar 

  50. Di Nardo, G. et al. Evidence for an elevated aspartate pKa in the active site of human aromatase. J. Biol. Chem. 290, 1186–1196 (2015).

    Article  Google Scholar 

  51. Son, S. et al. Repurposing macitentan with nanoparticle modulates tumor microenvironment to potentiate immune checkpoint blockade. Biomaterials 276, 121058 (2021).

    Article  CAS  Google Scholar 

  52. Quah, B. J. C., Warren, H. S. & Parish, C. R. Monitoring lymphocyte proliferation in vitro and in vivo with the intracellular fluorescent dye carboxyfluorescein diacetate succinimidyl ester. Nat. Protoc. 2, 2049–2056 (2017).

    Article  Google Scholar 

  53. Miller, I. C. et al. Enhanced intratumoural activity of CAR T cells engineered to produce immunomodulators under photothermal control. Nat. Biomed. Eng. 5, 1348–1359 (2021).

    Article  CAS  Google Scholar 

  54. Allen, I. C. Mouse Models of Innate Immunity: Methods and Protocols (Humana Press, 2013).

  55. Ma, Z. et al. Augmentation of immune checkpoint cancer immunotherapy with IL18. Clin. Cancer Res. 22, 2969–2980 (2016).

    Article  CAS  Google Scholar 

  56. Ganesh, S. et al. RNAi-mediated β-catenin inhibition promotes T cell infiltration and antitumor activity in combination with immune checkpoint blockade. Mol. Ther. 26, 2567–2579 (2018).

    Article  CAS  Google Scholar 

  57. Ruan, H. et al. A dual‐bioresponsive drug‐delivery depot for combination of epigenetic modulation and immune checkpoint blockade. Adv. Mater. 31, 1806957 (2019).

    Article  Google Scholar 

Download references

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.

Author information

Authors and Affiliations

Authors

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.

Ethics declarations

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.

Peer review

Peer review information

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

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Supplementary Information

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

Reporting Summary

Source data

Source Data Fig. 1

Statistical source data for Fig. 1b–g.

Source Data Fig. 2

Statistical source data for Fig. 2b,d,f,h.

Source Data Fig. 3

Statistical source data for Fig. 3b,c,e.

Source Data Fig. 4

Statistical source data for Fig. 4a,c,e,g,h.

Source Data Fig. 5

Statistical source data for Fig. 5c.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41563-023-01515-2

This article is cited by

Search

Quick links

Nature Briefing: Translational Research

Sign up for the Nature Briefing: Translational Research newsletter — top stories in biotechnology, drug discovery and pharma.

Get what matters in translational research, free to your inbox weekly. Sign up for Nature Briefing: Translational Research