Department of Digestive Tumor, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, China.
Centre of Neurological and Metabolic Research, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian, China.
Front Immunol. 2023 Sep 11;14:1227150. doi: 10.3389/fimmu.2023.1227150. eCollection 2023.
Hepatocellular carcinoma (HCC), the most common primary malignancy of the liver, is one of the leading causes of cancer-related death and is associated with a poor prognosis. The tumor microenvironment (TME) of HCC comprises immune, immunosuppressive, and interstitial cells with hypoxic, angiogenic, metabolic reprogramming, inflammatory, and immunosuppressive features. Exosomes are nanoscale extracellular vesicles that secrete biologically active signaling molecules such as deoxyribonucleic acid (DNA), messenger ribonucleic acid (mRNA), microribonucleic acid (miRNA), proteins, and lipids. These signaling molecules act as messengers in the tumor microenvironment, especially the tumor immunosuppressive microenvironment. Exosomal circRNAs reshape the tumor microenvironment by prompting hypoxic stress response, stimulating angiogenesis, contributing to metabolic reprogramming, facilitating inflammatory changes in the HCC cells and inducing tumor immunosuppression. The exosomes secreted by HCC cells carry circRNA into immune cells, which intervene in the activation of immune cells and promote the overexpression of immune checkpoints to regulate immune response, leading tumor cells to acquire immunosuppressive properties. Furthermore, immunosuppression is the final result of a combination of TME-related factors, including hypoxia, angiogenesis, metabolic reprogramming, and inflammation changes. In conclusion, exosomal circRNA accelerates the tumor progression by adjusting the phenotype of the tumor microenvironment and ultimately forming an immunosuppressive microenvironment. HCC-derived exosomal circRNA can affect HCC cell proliferation, invasion, metastasis, and induction of chemoresistance. Therefore, this review aimed to summarize the composition and function of these exosomes, the role that HCC-derived exosomal circRNAs play in microenvironment formation, and the interactions between exosomes and immune cells. This review outlines the role of exosomal circRNAs in the malignant phenotype of HCC and provides a preliminary exploration of the clinical utility of exosomal circRNAs.
肝细胞癌（HCC）是肝脏最常见的原发性恶性肿瘤，是癌症相关死亡的主要原因之一，预后不良。HCC 的肿瘤微环境（TME）由免疫、免疫抑制和间质细胞组成，具有缺氧、血管生成、代谢重编程、炎症和免疫抑制特征。外泌体是一种纳米级细胞外囊泡，可分泌具有生物活性的信号分子，如脱氧核糖核酸（DNA）、信使核糖核酸（mRNA）、微小核糖核酸（miRNA）、蛋白质和脂质。这些信号分子作为肿瘤微环境中的信使，特别是肿瘤免疫抑制微环境中的信使。外泌体 circRNA 通过促使缺氧应激反应、刺激血管生成、促进代谢重编程、促进 HCC 细胞炎症变化以及诱导肿瘤免疫抑制来重塑肿瘤微环境。HCC 细胞分泌的外泌体将 circRNA 带入免疫细胞，干预免疫细胞的激活，并促进免疫检查点的过度表达，以调节免疫反应，导致肿瘤细胞获得免疫抑制特性。此外，免疫抑制是 TME 相关因素（包括缺氧、血管生成、代谢重编程和炎症变化）综合作用的最终结果。总之，外泌体 circRNA 通过调节肿瘤微环境的表型加速肿瘤进展，最终形成免疫抑制微环境。HCC 来源的外泌体 circRNA 可影响 HCC 细胞的增殖、侵袭、转移和诱导化疗耐药性。因此，本综述旨在总结这些外泌体的组成和功能、HCC 来源的外泌体 circRNA 在微环境形成中的作用以及外泌体与免疫细胞之间的相互作用。本综述概述了外泌体 circRNA 在 HCC 恶性表型中的作用，并对外泌体 circRNA 的临床应用进行了初步探讨。
