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.

肿瘤来源的外泌体 (T-EXO) 阻碍免疫检查点阻断疗法，促使药理学努力抑制它们。受抗病毒曲率感应肽如何破坏外泌体大小范围内的膜包膜病毒颗粒的启发，我们设计了一种广泛有用的策略，重新利用工程化的抗病毒肽来破坏膜包膜的 T-EXO，以实现协同癌症免疫治疗。膜靶向肽抑制各种癌症类型的 T-EXO，并表现出与肿瘤微环境相关的 pH 值增强的膜破坏。T-EXO 破坏肽和基于程序性细胞死亡蛋白 1 抗体的免疫检查点阻断疗法的组合改善了荷瘤小鼠的治疗结果。⁺ T 细胞效应子功能，防止转移前生态位形成并重塑体内肿瘤微环境。我们的研究结果表明，肽诱导的 T-EXO 耗竭可以增强癌症免疫治疗，并支持肽工程在外泌体靶向应用中的潜力。