Chen Ruoqi, Chen Lianqing, Tang Yu, Shen Xiaolin, Wang Yajie, Tang Peng, Shentu Xingchao, Sun Jie
Eye Center of Second Affiliated Hospital, School of Medicine, Zhejiang University, Zhejiang Provincial Key Laboratory of Ophthalmology, Zhejiang Provincial Clinical Research Center for Eye Diseases. Zhejiang Provincial Engineering Institute on Eye Diseases, Hangzhou, China.
Liangzhu Laboratory, Zhejiang University, Hangzhou, China.
JCI Insight. 2025 Jul 22;10(14). doi: 10.1172/jci.insight.193048.
Transcription factors (TFs) play a pivotal role in the development and differentiation of T cells. Recent studies have highlighted unique transcriptional profiles in chimeric antigen receptor T (CAR-T) cells derived from patients with favorable clinical outcomes, suggesting a potential link between TF modulation and improved therapeutic efficacy. Although CAR-T cell therapies have shown some success in treating hematological malignancies, they are limited by challenges such as poor persistence, functional exhaustion, and tumor resistance. To overcome these limitations, researchers have attempted to enhance the efficacy of CAR-T cells through manipulation of TF expression. This Review provides a comprehensive overview of TF engineering in CAR-T cells and elucidates the complex regulatory network between TFs. Notably, modification of basic leucine zipper ATF-like transcription factor in CAR-T cells results in contradictory functional outcomes in different studies. We summarize the potential factors leading to such results and elucidate the importance of setting up a relevant in vitro model to evaluate the effect of TFs on CAR-T cells. In conclusion, this Review highlights the latest advances in TF modifications and proposes strategies for harnessing these insights to empower CAR-T cells with superior antitumor efficacy.
转录因子（TFs）在T细胞的发育和分化中起着关键作用。最近的研究突出了来自临床预后良好患者的嵌合抗原受体T（CAR-T）细胞中的独特转录谱，提示TF调节与治疗效果改善之间存在潜在联系。尽管CAR-T细胞疗法在治疗血液系统恶性肿瘤方面已取得一些成功，但它们受到诸如持久性差、功能耗竭和肿瘤抗性等挑战的限制。为克服这些限制，研究人员试图通过操纵TF表达来提高CAR-T细胞的疗效。本综述全面概述了CAR-T细胞中的TF工程，并阐明了TF之间复杂的调控网络。值得注意的是，在不同研究中，CAR-T细胞中碱性亮氨酸拉链ATF样转录因子的修饰导致了相互矛盾的功能结果。我们总结了导致这些结果的潜在因素，并阐明了建立相关体外模型以评估TF对CAR-T细胞影响的重要性。总之，本综述突出了TF修饰的最新进展，并提出了利用这些见解赋予CAR-T细胞卓越抗肿瘤疗效的策略。
