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

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, researchers at Sungkyunkwan University 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. These findings demonstrate that peptide-induced T-EXO depletion can enhance cancer immunotherapy and support the potential of peptide engineering for exosome-targeting applications.

Repurposed antiviral AH-D peptide disrupts T-EXOs
with enhanced activity under tumour pH conditions

Fig. 1

a, Illustration of T-EXO depletion strategy. b, NTA-tracked change in normalized number concentration of T-EXOs from human and murine cancer cells following T-EXO incubation with 1 μM AH-D or NH-D peptide for 10 min. WM-266, MDA-MB-231, B16F10 and 4T1 are human melanoma, human breast cancer, murine melanoma and murine breast cancer cell lines, respectively. c,d, Corresponding NTA results for B16F10-derived T-EXOs following incubation with 1 μM AH-D or NH-D peptide for different time intervals (c) or for 5 min under varying pH (d). bd, Results reported as mean ± s.d. (n = 3 biological replicates, one-way analysis of variance (ANOVA)). e,f, Maximal QCM-D changes in resonance frequency (e) and energy dissipation (f) signals following the addition of 32 μM AH-D peptide to a layer of surface-adsorbed liposomes under varying pH. e,f, Results reported as mean ± s.d. (n = 4 biological replicates, one-way ANOVA). g, Binding cooperativity of AH-D peptide-induced liposomal membrane rupture under varying pH. Results reported as best-fit values ± s.d. from least-squares regression (n = 16 independent experiments, one-sided extra sum-of-squares F-tests between groups). h, Change in Gibbs free energy for membrane partitioning of AH-D peptide under varying pH. Modelling based on the Wimley–White interfacial hydrophobicity scale; dashed lines correspond to all charged (top) or all neutral (bottom) Asp residues in the peptide.

Shin S, Ko H, Kim CH, Yoon BK, Son S, Lee JA, Shin JM, Lee J, Song SH, Jackman JA, Park JH. (2023) Curvature-sensing peptide inhibits tumour-derived exosomes for enhanced cancer immunotherapy. Nat Mater [Epub ahead of print]. [abstract]

Leave a Reply

Your email address will not be published. Required fields are marked *