《生命科学》 2025, 37(8): 992-1006

细胞因子信号系统的人工设计与临床应用

姜思琦¹ , 周佳玲¹ , 冯安南¹ , 雷海邦¹ , 郭　伟¹ , 王　苗¹ , 姜源旭^1,2 , 魏　平^1,2,*

¹中国科学院深圳先进技术研究院，合成生物学研究所，细胞与基因线路设计中心， 深圳 518055 ²北京大学前沿交叉学科研究院，定量生物学中心，北京 100871

摘　要：

细胞因子作为免疫调控的核心介质，在肿瘤、自身免疫病等疾病的治疗中具有重要潜力，但其临床应用长期受限于多效性强、半衰期短、毒性大和靶向性不足等问题。近年来，合成生物学和蛋白质工程的发展为细胞因子的人工改造提供了全新策略。研究者通过配体结构域定向进化与从头设计，成功构建了具有延长血浆半衰期和增强靶向特异性的新型细胞因子变体；利用计算生物学指导的重组受体工程，实现了下游信号通路的正交性激活与可编程信号输出；更有基于模块化生物元件开发的智能调控系统，能够通过生物传感器介导的反馈回路精确控制细胞因子的时空释放。这些创新技术体系正在推动细胞因子治疗从传统的天然分子替代向人工智能驱动的精准调控范式跃迁，为肿瘤微环境重编程、自身免疫稳态重建等重大医学挑战提供变革性解决方案。

通讯作者：魏　平 , Email:ping.wei@siat.ac.cn

Artificial design and clinical applications of the cytokine signaling system

JIANG Si-Qi¹ , ZHOU Jia-Ling¹ , FENG An-Nan¹ , LEI Hai-Bang¹ , GUO Wei¹ , WANG Miao¹ , JIANG Yuan-Xu^1,2 , WEI Ping^1,2,*

¹Center for Cell and Gene Circuit Design, CAS Key Laboratory of Quantitative Engineering Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China ²Center for Quantitative Biology, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100871, China

Abstract:

Cytokines serve as core mediators of immune regulation and hold significant potential for treating diseases such as cancer and autoimmune disorders. However, their clinical application has long been hindered by challenges including pleiotropic effects, short half-life, high toxicity, and insufficient targeting specificity. Recent advances in synthetic biology and protein engineering have provided novel strategies for the artificial modification of cytokines. By engineering and designing new cytokine ligands, their half-life can be extended and specificity can be enhanced. Additionally, through the design of recombinant cytokine receptors, downstream signaling can be orthogonally activated to generate precisely regulated outputs. Artificial cytokine signaling circuits based on modular platforms such as synNotch and MESA enable intelligent and precise cytokine release. These innovative technologies are driving a paradigm shift in cytokine therapy—from natural molecule replacement to rational design—offering breakthrough advancements in cancer immunotherapy, autoimmune diseases, and beyond.

Communication Author：WEI Ping , Email:ping.wei@siat.ac.cn