合成生物学使得重新调整自然细胞反应以治疗疾病成为可能，尤其是由嵌合抗原受体（CAR）T细胞表现出的癌症免疫疗法。基于合成受体成功激活T细胞的经验，该领域现在研究了如何诱导非规范信号通路和复杂的合成基因电路，以增强工程T细胞的抗肿瘤表型。本评论探讨了两项最近发表的研究，为新技术如何实现这一目标提供了概念验证。第一个研究表明，以CAR为基础的来自各种免疫受体的信号模体的非自然组合，可在T细胞中驱动独特的信号传导途径，并提高它们的肿瘤杀伤能力。在这里，机器学习辅助筛选过程，并成功预测了依赖于信号模体选择的CAR T细胞表型。第二个研究则探讨了合成锌手指如何被设计成可控的转录调节因子，其活性取决于是否存在FDA核准的小分子药物。这些研究在扩展未来基因电路的设计选择方面具有关键作用，并强调了单一细胞治疗如何对多个环境线索进行响应，包括靶细胞抗原表达、肿瘤微环境组成和小分子药物。© 2023 John Wiley＆Sons Ltd代表欧洲生化联合会出版的分子肿瘤学。

Synthetic biology has made it possible to rewire natural cellular responses to treat disease, notably demonstrated by chimeric antigen receptor (CAR) T cells as cancer immunotherapy. Building on the success of T-cell activation using synthetic receptors, the field is now investigating how induction of noncanonical signalling pathways and sophisticated synthetic gene circuitry can enhance the antitumour phenotype of engineered T cells. This commentary explores two recently published studies that provide proof of concept for how new technologies achieve this. The first demonstrated that non-naturally occurring combinations of signalling motifs derived from various immune receptors and arranged as a CAR drove unique signal transduction pathways in T cells and improved their tumour killing ability. Here, machine learning complemented the screening process and successfully predicted CAR T-cell phenotype dependent on signalling motif choice. The second explored how synthetic zinc fingers can be engineered into controllable transcriptional regulators, where their activity was dependent on the presence or absence of FDA-approved small-molecule drugs. These studies are pivotal in expanding the design choices available for gene circuits of the future and highlight how a single cellular therapy could respond to multiple environmental cues including target cell antigen expression, the tumour microenvironment composition and small molecule drugs.© 2023 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.