Abstract：
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.
摘要：
环状RNA（circularRNAs）因其参与免疫逃逸和免疫疗法敏感性调节而受到关注。CircZNF609是各种实体瘤中众所周知的癌基因。我们先前的研究揭示了其在降低膀胱癌（BCa）对顺铂的化学敏感性中的作用。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细胞共培养试验，人免疫重建的细胞系来源的异种移植和患者来源的异种移植小鼠模型，以进一步证实circZNF609在BCa免疫逃逸和免疫疗法敏感性中的作用。circZNF609的过表达在体外和体内促进了BCa免疫逃逸。机械上,circZNF609与IGF2BP2结合，增强了其与CD363'-非翻译区的相互作用。这增加了CD36mRNA的稳定性，导致BCa细胞对脂肪酸的摄取增强和肿瘤微环境内的脂肪酸消耗。此外,cirzNF609的核出口受DDX39B管制。CircZNF609通过调节新发现的circZNF609/IGF2BP2/CD36级联，促进免疫逃逸并抑制BCa免疫治疗敏感性。因此,circZNF609在BCa免疫疗法中具有作为生物标志物和治疗靶标的潜力。
