揭示免疫抑制肿瘤微环境的机制并制定相应的治疗策略对于提高癌症免疫治疗具有重要意义。在这项研究中，我们发现结肠癌组织中积累了丰富的衰老细胞，这对免疫抑制微环境有很大贡献。口服达沙替尼和槲皮素 (D Q) 可以消除衰老细胞，但由于肿瘤渗透性差和半衰期短，效率较低。为了提高衰老细胞清除的功效，我们开发了一种基于细胞外囊泡（EV）的衰老策略。工程化的 senolytic EV 表面显示有抗 GPNMB（一种衰老细胞表面标记物），膜上负载有 D Q。在同基因小鼠模型中，senolytic EVs 有效且选择性地根除衰老细胞，进而释放抗肿瘤免疫力。随着抗肿瘤免疫力的增强，癌症的生长受到抑制，生存期得以延长。总之，我们在此阐明了衰老细胞对结肠癌中免疫抑制微环境的影响，并提出了一种通过基于 EV 的 senolytics 来克服该问题的新策略。本文受版权保护。保留所有权利。本文受版权保护。版权所有。

Unravelling the mechanisms for the immunosuppressive tumor microenvironment and developing corresponding therapeutic strategies are of great importance to improve the cancer immunotherapy. In this study, we have revealed that there are abundant senescent cells accumulated in the colon cancer tissue, which contributes greatly to the immunosuppressive microenvironment. Oral delivery of Dasatinib and Quercetin (D+Q) eliminates the senescent cells with compromised efficiency due to the poor tumor penetration and short half-life. To improve the efficacy of senescent cell clearance, we have developed an extracellular vesicle (EV)-based senolytic strategy. The engineered senolytic EVs have anti-GPNMB (a senescent cell surface marker) displayed on the surface and D+Q loaded on the membrane. In a syngeneic mouse model, senolytic EVs efficiently and selectively eradicate the senescent cells and in turn unleashes the antitumor immunity. With the antitumor immunity boosted, cancer growth is inhibited and the survival is prolonged. In summary, we here have illuminated that senescent cells contribute to the immunosuppressive microenvironment in colon cancer and proposed a novel strategy to conquer the problem by EV-based senolytics. This article is protected by copyright. All rights reserved.This article is protected by copyright. All rights reserved.