CAR-T（CAR-T）细胞疗法在非肿瘤性疾病中的应用
Chimeric antigen receptor T (CAR-T) cell therapy in non-oncological diseases.
CAR-T（CAR-T）细胞在血液系统恶性肿瘤中的应用推动了这种免疫治疗形式的显著进展。
CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
通过结构域重组设计的合成转录因子增强 CAR-T 细胞的抗肿瘤功能
英文原题：Synthetic transcription factors designed by domain recombination enhance CAR T cell antitumor function.
查看英文原题
Synthetic transcription factors designed by domain recombination enhance CAR T cell antitumor function.
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中文摘要
人类蛋白编码基因通过来自祖先基因的结构域重排而进化。我们开发了一种可扩展的、进化引导的方法，从同一蛋白家族内的组成结构域组装新基因，称为 DESynR（通过合成和重组进行结构域工程化）基因。在原代人 T 细胞中，DESynR 激活蛋白-1（AP-1）转录因子（TFs）在体外和体内抗肿瘤试验中显著优于天然 AP-1 TFs。DESynR AP-1 TFs 诱导广泛的转录和表观遗传重编程，并建立非天然 T 细胞状态，这些状态优化耗竭、效应和细胞毒功能以及持续性等特征——有时会征用来自不同细胞类型的基因模块。重编程主要由对已建立的 AP-1 结合调控元件的差异性调控驱动，而非独特结合。
最后，我们筛选 DESynR 红细胞转化特异性（ETS）和叉头框（FOX）TFs，以支持跨蛋白家族的普适性。总体而言，我们证明，重新配置现有的蛋白结构域可能发现非进化产生的基因，这些基因可编程具有治疗相关性的细胞状态。
展开英文摘要原文
Human protein-coding genes evolved via rearrangement of domains from ancestral genes.
We develop a scalable, evolutionarily guided method to assemble novel genes from constituent domains within a protein family, termed DESynR (domain engineered via synthesis and recombination) genes. In primary human T cells, DESynR activator protein-1 (AP-1) transcription factors (TFs) significantly outperform natural AP-1 TFs across in vitro and in vivo antitumor assays.
DESynR AP-1 TFs induce broad transcriptional and epigenetic reprogramming and establish non-natural T cell states that optimize features of exhaustion, effector and cytotoxic function, and persistence-sometimes co-opting gene modules from disparate cell types. Reprogramming is primarily driven by differential regulation of established AP-1-bound regulatory elements rather than unique binding.
Finally, we screen DESynR erythroblast transformation-specific (ETS) and forkhead box (FOX) TFs to support generalizability across protein families.
Overall, we demonstrate that reconfiguring existing protein domains may uncover non-evolved genes that program therapeutically relevant cell states.
论文信息
- 作者
- Takacsi-Nagy O、Kasinathan S、Hartman A、Yin Y、Wu L、Chen AY、Moser LM、May AP
- 第一作者单位
- Department of Pathology, Stanford University, Stanford, CA, USA; Center for Immunotherapy Design, Stanford University, Stanford, CA, USA; Program in Immunology, Stanford University, Stanford, CA, USA.United States
- 通讯作者单位
- Department of Pathology, Stanford University, Stanford, CA, USA; Center for Immunotherapy Design, Stanford University, Stanford, CA, USA; Program in Immunology, Stanford University, Stanford, CA, USA; Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA; Weill Cancer Hub West, Stanford, CA, USA. Electronic address: satpathy@stanford.edu.United States
- 期刊
- Cell2026 Aug 19
- 原文标识
- PubMed 42617595 · DOI 10.1016/j.cell.2026.07.054