癌症凭借较差的免疫原性逃避宿主的免疫监视。在这里，我们报告了一种免疫抑制剂，称为 PTIR1，它充当肿瘤免疫抵抗的促进剂。 PTIR1通过DDX58（RIG-I）的选择性剪接在人类癌症中被选择性诱导，其诱导与癌症患者的不良预后密切相关。通过阻止白细胞的募集，PTIR1 促进癌症免疫逃逸和肿瘤对免疫治疗的内在抵抗。与 RIG-I 不同，PTIR1 能够结合 UCHL5 的 C 末端并激活其泛素化功能，进而抑制免疫蛋白酶体活性并限制新抗原的加工和呈递，从而阻止 T 细胞识别和攻击癌症。此外，我们发现腺苷脱氨酶 ADAR1 诱导 DDX58 转录本上的 A 到 I RNA 编辑，从而触发 PTIR1 的产生。总的来说，我们的数据揭示了 PTIR1 在肿瘤发生中的免疫抑制作用，并提出 ADAR1-PTIR1-UCHL5 信号传导是潜在的癌症免疫治疗靶点。版权所有 © 2023 作者。由爱思唯尔公司出版。保留所有权利。

Cancer evades host immune surveillance by virtue of poor immunogenicity. Here, we report an immune suppressor, designated as PTIR1, that acts as a promotor of tumor immune resistance. PTIR1 is selectively induced in human cancers via alternative splicing of DDX58 (RIG-I), and its induction is closely related to poor outcome in patients with cancer. Through blocking the recruitment of leukocytes, PTIR1 facilitates cancer immune escape and tumor-intrinsic resistance to immunotherapeutic treatments. Unlike RIG-I, PTIR1 is capable of binding to the C terminus of UCHL5 and activates its ubiquitinating function, which in turn inhibits immunoproteasome activity and limits neoantigen processing and presentation, consequently blocking T cell recognition and attack against cancer. Moreover, we find that the adenosine deaminase ADAR1 induces A-to-I RNA editing on DDX58 transcript, thus triggering PTIR1 production. Collectively, our data uncover the immunosuppressive role of PTIR1 in tumorigenesis and propose that ADAR1-PTIR1-UCHL5 signaling is a potential cancer immunotherapeutic target.Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.