胰腺导管腺癌（PDAC）的特点是免疫逃避，导致预后不良。癌症相关成纤维细胞 (CAF) 在协调 PDAC 肿瘤微环境中发挥着关键作用。我们研究了 CAF 衍生的细胞外囊泡 (EV) 包装的长非编码 RNA (lncRNA) 在免疫逃避中的作用，并探索了使用装载小干扰 RNA (siRNA) 的工程化 EV 进行基因治疗作为潜在的治疗策略。我们的研究结果强调了来自 CAF 的 EV 包装的 lncRNA RP11-161H23.5 在通过下调 HLA-A 表达（抗原呈递的关键组成部分）促进 PDAC 免疫逃避方面的重要性。从机制上讲，RP11-161H23.5 与 CNOT4（mRNA 去腺苷酸酶 CCR4-NOT 复合物的亚基）形成复合物，通过缩短其 Poly(A) 尾来增强 HLA-A mRNA 的降解。这种免疫逃避机制会损害抗肿瘤免疫反应。为了解决这个问题，我们提出了一种创新方法，利用工程化的 EV 作为基于 siRNA 的基因治疗的天然和生物相容性纳米载体，该策略有望提高 PDAC 免疫治疗的有效性。总体而言，我们的研究揭示了 CAF 衍生的 EV 包装的 lncRNA RP11-161H23.5/CNOT4/HLA-A 轴在 PDAC 免疫逃避中的关键作用，并提出了一种新的治疗干预途径。© 2024 。 《Journal of Extracellular Vesicles》由 Wiley periodicals LLC 代表国际细胞外囊泡学会出版。

Pancreatic ductal adenocarcinoma (PDAC) is characterised by immune evasion that contribute to poor prognosis. Cancer-associated fibroblasts (CAFs) play a pivotal role in orchestrating the PDAC tumour microenvironment. We investigated the role of CAF-derived extracellular vesicle (EV)-packaged long non-coding RNAs (lncRNAs) in immune evasion and explored gene therapy using engineered EVs loading small interfering RNAs (siRNAs) as a potential therapeutic strategy. Our findings highlight the significance of EV-packaged lncRNA RP11-161H23.5 from CAF in promoting PDAC immune evasion by downregulating HLA-A expression, a key component of antigen presentation. Mechanistically, RP11-161H23.5 forms a complex with CNOT4, a subunit of the mRNA deadenylase CCR4-NOT complex, enhancing the degradation of HLA-A mRNA by shortening its poly(A) tail. This immune evasion mechanism compromises the anti-tumour immune response. To combat this, we propose an innovative approach utilising engineered EVs as natural and biocompatible nanocarriers for siRNA-based gene therapy and this strategy holds promise for enhancing the effectiveness of immunotherapy in PDAC. Overall, our study sheds light on the critical role of CAF-derived EV-packaged lncRNA RP11-161H23.5/CNOT4/HLA-A axis in PDAC immune evasion and presents a novel avenue for therapeutic intervention.© 2024 The Author(s). Journal of Extracellular Vesicles published by Wiley Periodicals LLC on behalf of International Society for Extracellular Vesicles.