Sol Shin1,9, Hyewon Ko2,3,9, Chan Ho Kim 4, Bo Kyeong Yoon4,5,6,7, Soyoung Son4, Jae Ah Lee4, Jung Min Shin8, Jeongjin Lee1, Seok Ho Song4, Joshua A. Jackman 4,5,6 & Jae Hyung Park 1,4,6
1Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, Republic of Korea.
2Bionanotechnology Research Center, Korea Research Institute of Bioscience & Biotechnology, Daejeon, Republic of Korea.
3School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea.
4School of Chemical Engineering, College of Engineering, Sungkyunkwan University, Suwon, Republic of Korea.
5Translational Nanobioscience Research Center, Sungkyunkwan University, Suwon, Republic of Korea.
6Biomedical Institute for Convergence at SKKU, Sungkyunkwan University, Suwon, Republic of Korea.
7School of Healthcare and Biomedical Engineering, Chonnam National University, Yeosu, Republic of Korea.
8Division of Biotechnology, Convergence Research Institute, DGIST, Daegu, Republic of Korea.
9These authors contributed equally: Sol Shin, Hyewon Ko.
Corresponding authors : Correspondence to Joshua A. Jackman or Jae Hyung Park.
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.