Department of Urology, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China.
Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
Int Immunopharmacol. 2024 Aug 20;137:112485. doi: 10.1016/j.intimp.2024.112485. Epub 2024 Jun 14.
Circular RNAs (circRNAs) are gaining attention for their involvement in immune escape and immunotherapy sensitivity regulation. CircZNF609 is a well-known oncogene in various solid tumours. Our previous research revealed its role in reducing the chemosensitivity of bladder cancer (BCa) to cisplatin. However, the underlying role of circZNF609 in BCa immune escape and immunotherapy sensitivity remains unknown. We conducted BCa cells-CD8 + T cells co-culture assays, cell line-derived xenograft and patient-derived xenograft mouse models with human immune reconstitution to further confirm the role of circZNF609 in BCa immune escape and immunotherapy sensitivity. Overexpression of circZNF609 promoted BCa immune escape in vitro and in vivo. Mechanistically, circZNF609 was bound to IGF2BP2, enhancing its interaction with the 3'-untranslated region of CD36. This increased the stability of the CD36 mRNA, leading to enhanced fatty acid uptake by BCa cells and fatty acid depletion within the tumour microenvironment. Additionally, the nuclear export of circZNF609 was regulated by DDX39B. CircZNF609 promoted immune escape and suppressed BCa immunotherapy sensitivity by regulating the newly identified circZNF609/IGF2BP2/CD36 cascade. Therefore, circZNF609 holds potential as both a biomarker and therapeutic target in BCa immunotherapy.
环状 RNA（circRNAs）因其参与免疫逃逸和免疫治疗敏感性调节而受到关注。CircZNF609 是各种实体瘤中一种众所周知的癌基因。我们之前的研究表明它在降低膀胱癌（BCa）对顺铂的化疗敏感性方面发挥作用。然而，circZNF609 在 BCa 免疫逃逸和免疫治疗敏感性中的潜在作用尚不清楚。我们进行了 BCa 细胞-CD8+T 细胞共培养实验、细胞系衍生的异种移植和患者来源的异种移植小鼠模型，并用人类免疫重建来进一步证实 circZNF609 在 BCa 免疫逃逸和免疫治疗敏感性中的作用。circZNF609 的过表达促进了 BCa 的体外和体内免疫逃逸。在机制上，circZNF609 与 IGF2BP2 结合，增强了它与 CD36 的 3'-非翻译区的相互作用。这增加了 CD36 mRNA 的稳定性，导致 BCa 细胞摄取更多的脂肪酸，并使肿瘤微环境中的脂肪酸耗竭。此外，circZNF609 的核输出受 DDX39B 调节。CircZNF609 通过调节新发现的 circZNF609/IGF2BP2/CD36 级联反应，促进免疫逃逸并抑制 BCa 免疫治疗的敏感性。因此，circZNF609 有望成为 BCa 免疫治疗中的一种生物标志物和治疗靶点。
