《生命科学》 2025, 37(8): 962-971
肿瘤响应人工基因线路设计及其在溶瘤病毒治疗中的应用
摘 要:
传统放化疗及免疫检查点抑制剂仅对部分肿瘤患者有效,嵌合抗原受体T 细胞(chimeric antigen receptor T-cell, CAR-T) 等细胞疗法在实体瘤中则因缺乏特异性抗原、免疫抑制微环境及组织屏障等因素,疗效受限。大量关键肿瘤标志物位于细胞内部,常规免疫识别策略难以靶及,进一步限制治疗精准性。合成生物学通过模块化设计与人工智能优化,构建“感知- 决策- 执行”闭环的肿瘤响应型基因线路,借助逻辑门整合乏氧、异常信号通路、肿瘤特异性表达的转录因子和微小RNA (microRNA, miRNA) 等多维输入,实现多重判别与高特异性杀伤。溶瘤病毒(oncolytic viruses, OVs) 因天然肿瘤趋向性与免疫激活作用,成为实体瘤基因治疗的重要平台。将人工合成基因线路嵌入OVs 构建智能溶瘤病毒,可在肿瘤特异环境下精准启动复制与治疗基因表达,并结合光遗传学或小分子开关实现时空调控。本文综述肿瘤响应型基因线路的设计原则,梳理智能溶瘤病毒的转化进展及其与免疫检查点抑制剂、CAR-T 和放疗的联合策略,探讨容量受限、全身递送效率低与宿主免疫干扰等挑战,并展望人工智能辅助设计与新型递送平台的发展前景。
通讯作者:叶海峰 , Email:hfye@bio.ecnu.edu.cn
Abstract:
Conventional chemotherapy, radiotherapy, and immune checkpoint inhibitors benefit only a subset of cancer patients, while cell therapies such as CAR-T are often ineffective against solid tumors due to the lack of tumor-specific antigens, immunosuppressive microenvironments, and physical tissue barriers. A significant number of critical tumor markers are located intracellularly, limiting the precision of conventional immune recognition strategies. Synthetic biology offers new opportunities to address these challenges by constructing tumor-responsive gene circuits with a sense-process-actuate” architecture. These circuits, designed through modular engineering and optimized via artificial intelligence, integrate multidimensional inputs, such as hypoxia, aberrant signaling pathways, tumor‑specific transcription factors, and microRNAs (miRNAs) through logic-gated computation to achieve high-specificity tumor discrimination and cytotoxicity. Oncolytic viruses (OVs), owing to their inherent tumor tropism and immune-stimulating properties, have emerged as a powerful platform for gene therapy in solid tumors. By embedding synthetic gene circuits into OVs, intelligent oncolytic viruses can be engineered to initiate replication and therapeutic gene expression specifically within the tumor microenvironment, with additional spatiotemporal control enabled by optogenetic or small-molecule switches. This review outlines the design principles of tumor-responsive gene circuits, summarizes the translational advances of intelligent oncolytic viruses, and discusses their synergistic potential when combined with immune checkpoint blockade, CAR-T therapy, and
radiotherapy. Furthermore, it addresses major challenges such as limited cargo capacity, inefficient systemic delivery, and host immune interference, while highlighting future directions involving AI-assisted circuit design and next-generation delivery platforms.
Communication Author:YE Hai-Feng , Email:hfye@bio.ecnu.edu.cn