Abstract:

Immunotherapy has revolutionized modern medicine by harnessing the body's immune system to combat malignancies, infectious diseases, and autoimmune disorders. Despite remarkable clinical successes, current immunotherapeutic approaches face substantial limitations, including inadequate target specificity, dysregulated immune activation, and severe systemic toxicities. These challenges stem from the inherent complexity of biological systems and the pleiotropic nature of immune responses. Synthetic biology emerges as a transformative paradigm to address these limitations through rational engineering of immune cells and circuits. This discipline applies engineering principles to biological systems, enabling the design of sophisticated genetic circuits that confer precise spatiotemporal control over immune functions. This review comprehensively examines current synthetic biology strategies in immunotherapy, highlighting their mechanistic basis, clinical applications, and future directions for advancing precision medicine. Key innovations include: (1) engineered receptor systems (e.g., Syn-Notch, RASSL) that implement Boolean logic operations for enhanced target discrimination; (2) synthetic signaling cascades (e.g., CHOMP, SPOC) that convert pathological signals into therapeutic outputs; and (3) feedback-regulated circuits that dynamically modulate immune effector functions. These technologies have been successfully implemented in chimeric antigen receptor (CAR)-based therapies, where they improve tumor specificity while mitigating cytokine release syndrome and other adverse effects. Notably, synthetic biology facilitates the development of "smart" immunotherapies capable of environmental sensing, decision-making, and self-regulation. For instance, conditionally activated CAR-T cells demonstrate improved safety profiles through drug-inducible control systems, while synthetic cytokine circuits enable precise immune modulation. Furthermore, the integration of computational modeling with high-throughput screening accelerates the optimization of these engineered systems. Looking forward, synthetic biology promises to bridge critical gaps in conventional immunotherapy by enabling: (1) personalized therapeutic regimens through patient-specific circuit design; (2) multi-input diagnostic capabilities for complex disease microenvironments; and (3) robust safety mechanisms to prevent off-target effects. As the field progresses, the convergence of genome editing, biomaterials science, and artificial intelligence will further expand the therapeutic potential of engineered immune cells.

Key words: immunotherapy, synthetic biology, genetic circuits, cancer immunotherapy

摘要：

免疫治疗近年来在肿瘤、感染性疾病和自身免疫病等领域取得了突破性进展，但其临床应用仍面临信号识别特异性不足、免疫反应调控不精准及毒副作用显著等挑战。合成生物学作为一门新兴的工程化学科，通过模块化设计和基因回路编程，为免疫治疗的精准化改造提供了创新解决方案。本文系统综述了合成生物学在免疫治疗中的关键技术、应用案例及未来方向，旨在为免疫治疗的工程化设计提供理论依据和技术参考。在信号输入环节，工程化受体（如Syn-Notch、RASSL）通过逻辑门控设计（如“与”门）增强靶向性，减少脱靶效应；在信号处理环节，人工基因回路（如CHOMP、SPOC）将病理信号转化为治疗性输出，实现选择性杀伤或动态调控；在信号输出环节，反馈系统和振荡回路（如负反馈抑制T细胞过度活化）优化免疫反应强度与时长，提升安全性。此外，合成生物学技术已成功应用于CAR-T、CAR-NK等细胞疗法，通过受体改造、回路重编程等手段，显著提高了疗效并降低了毒性。未来，随着基因编辑、动态调控等技术的进一步发展，合成生物学驱动的免疫治疗将推动精准医学的实现，为复杂疾病的治疗提供更高效、更安全的策略。

关键词: 免疫治疗, 合成生物学, 基因回路, 癌症免疫治疗