Lai Yongping, Wang Fei, Cai Guang, Li Yingying, Weng Jiaxin, Cai Feifan, Cai Leijie, Cheng Niangmei, Zhao Bixing, Zeng Yongyi
Department of Hepatopancreatobiliary Surgery, First Affiliated Hospital of Fujian Medical University, Fuzhou, China.
Department of Hepatobiliary Pancreatic Surgery, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian, China.
Front Immunol. 2025 Jun 11;16:1609165. doi: 10.3389/fimmu.2025.1609165. eCollection 2025.
Hepatocellular carcinoma (HCC) is characterized by a complex interplay of genetic and epigenetic alterations that contribute to its aggressive nature and resistance to conventional therapies. The recent advent of immune checkpoint inhibitors has shown promise in enhancing the immune system's ability to target cancer cells. However, the efficacy of these therapies is often hindered by the tumor's immunosuppressive microenvironment. Circular RNAs (circRNAs), a class of non-coding RNAs, have emerged as promising candidates for the development of novel therapeutics due to their unique properties, including resistance to degradation and the ability to act as miRNA sponges.
In this study, we engineered artificial circRNAs to target oncogenic miRNAs and to express anti-PD-1 scFv antibodies, aiming to simultaneously disrupt oncogenic pathways and enhance the immune response against HCC.
Our results demonstrate that the engineered circRNAs effectively sponge miR-25, leading to subsequent inhibition of HCC cell proliferation and angiogenesis. Moreover, the expression of anti-PD-1 scFv antibodies from the circRNAs significantly enhanced the cytotoxic T-cell response against HCC cells. studies revealed a significant reduction in tumor volume and prolonged survival in mice treated with the engineered circRNAs compared to controls.
Our findings highlight the potential of artificial circRNAs as a novel therapeutic strategy for HCC. By harnessing their ability to act as miRNA sponges and to express immunomodulatory proteins, these engineered circRNAs offer a promising approach to overcome the challenges associated with HCC therapy.
肝细胞癌（HCC）的特征在于遗传和表观遗传改变的复杂相互作用，这些改变导致其侵袭性本质和对传统疗法的抗性。免疫检查点抑制剂的最新出现显示出增强免疫系统靶向癌细胞能力的前景。然而，这些疗法的疗效常常受到肿瘤免疫抑制微环境的阻碍。环状RNA（circRNA）是一类非编码RNA，由于其独特的性质，包括抗降解能力和充当miRNA海绵的能力，已成为新型治疗药物开发的有希望的候选者。
在本研究中，我们设计了人工circRNA以靶向致癌miRNA并表达抗PD-1单链抗体片段（scFv），旨在同时破坏致癌途径并增强针对HCC的免疫反应。
我们的结果表明，工程化的circRNA有效地充当miR-25的海绵，导致随后对HCC细胞增殖和血管生成的抑制。此外，circRNA表达的抗PD-1 scFv抗体显著增强了细胞毒性T细胞对HCC细胞的反应。研究显示，与对照组相比，用工程化circRNA处理的小鼠肿瘤体积显著减小，生存期延长。
我们的研究结果突出了人工circRNA作为HCC新型治疗策略的潜力。通过利用它们充当miRNA海绵和表达免疫调节蛋白的能力，这些工程化的circRNA为克服与HCC治疗相关的挑战提供了一种有前途的方法。
