Circular RNAs (circRNAs) play important roles in the regulation of cancer. However, the clinical implications and regulatory networks of circRNAs in cancer patients receiving immune checkpoint blockades (ICB) have not been fully elucidated. Here, we characterize circRNA expression profiles in two independent cohorts of 157 ICB-treated advanced melanoma patients and reveal overall overexpression of circRNAs in ICB non-responders in both pre-treatment and early during therapy. Then, we construct circRNA-miRNA-mRNA regulatory networks to reveal circRNA-related signaling pathways in the context of ICB treatment. Further, we construct an ICB-related circRNA signature (ICBcircSig) score model based on progression-free survival-related circRNAs to predict immunotherapy efficacy. Mechanistically, the overexpression of ICBcircSig circTMTC3 and circFAM117B could increase PD-L1 expression via the miR-142-5p/PD-L1 axis, thus reducing T cell activity and leading to immune escape. Overall, our study characterizes circRNA profiles and regulatory networks in ICB-treated patients, and highlights the clinical utility of circRNAs as predictive biomarkers of immunotherapy.

环状 RNA (circRNA) 在癌症的调控中起着重要作用。然而，circRNA 在接受免疫检查点阻断 (ICB) 的癌症患者中的临床意义和调控网络尚未完全阐明。在这里，我们描述了 157 名接受 ICB 治疗的晚期黑色素瘤患者的两个独立队列中的 circRNA 表达谱，并揭示了在治疗前和治疗早期 ICB 无反应者中 circRNA 的总体过表达。然后，我们构建了 circRNA-miRNA-mRNA 调控网络，以揭示 ICB 治疗背景下与 circRNA 相关的信号通路。此外，我们构建了一个基于无进展生存相关 circRNA 的 ICB 相关 circRNA 特征（ICBcircSig）评分模型来预测免疫治疗效果。从机械上讲，ICBcircSig circTMTC3 和 circFAM117B 的过表达可通过 miR-142-5p/PD-L1 轴增加 PD-L1 表达，从而降低 T 细胞活性并导致免疫逃逸。总体而言，我们的研究描述了接受 ICB 治疗的患者的 circRNA 概况和调控网络，并强调了 circRNA 作为免疫治疗预测生物标志物的临床效用。