爱丁堡大学Steven M. Pollard小组取得一项新突破。他们的研究发现合成超级增强剂使精确的病毒免疫治疗成为可能。相关论文于2026年4月8日发表在《自然》杂志上。

利用对增强子功能的最新见解，课题组通过将功能验证的增强子片段组装成多部分阵列来开发合成超级增强子（SSEs）。以胶质母细胞瘤干细胞（GSCs）中SOX2驱动和SOX9驱动的转录调控网络为基础，该研究团队设计了具有高活性和高选择性的SSE。单细胞分析、生化分析和基因组结合数据表明，SSE整合神经发育和信号状态转录因子，触发转录因子的大多聚体复合物的形成。

此外，GSC选择性表达细胞毒性（HSV-TK和更昔洛韦）和免疫调节（IL-12）有效载荷的组合，传递主题腺相关病毒载体，作为单一治疗，在侵袭性胶质母细胞瘤的单主题模型中取得了治愈结果。值得注意的是，IL-12诱导免疫记忆，防止肿瘤复发。腺相关病毒和SSE的活性和选择性在原发性人胶质母细胞瘤组织和正常皮质样品中得到验证。总之，SSE利用独特的核心转录程序来定义GSC表型并实现精确的免疫激活。当需要在特定细胞状态下精确控制转基因表达时，这种方法可能在其他情况下有更广泛的应用。

据悉，细胞类型特异性启动子是基因治疗的主题，以限制治疗有效载荷的表达。然而，这些启动子通常具有次优的强度、选择性和大小。

附：英文原文

Title: Synthetic super-enhancers enable precision viral immunotherapy

Author: Koeber, Ute, Matjusaitis, Mantas, Alfazema, Neza, Furlong, Katharine, Wang, Zeyu, White, Rachel, Hamdan, Alhafidz, Dewari, Pooran, Morisse, Gregoire, Navarette, Mariela, Willis, Rosie, Wang, Jin, Clark, Michelle P., Jacinto de Sousa, Carla, Hong, Hei Ip, Sheraz, Shahida, Southgate, Ben, Cholewa-Waclaw, Justyna, Gogolok, Sabine, Morrison, Gillian M., Cancino, Felipe Galvez, Robertson, Faye, Williams, Anna, Rosser, Susan J., Brennan, Paul M., Sieger, Dirk, Soufi, Abdenour, Quezada, Sergio A., Pollard, Steven M.

Issue&Volume: 2026-04-08

Abstract: Cell-type-specific promoters are used in gene therapy to restrict expression of the therapeutic payload. However, these promoters often have suboptimal strength, selectivity and size. Here, leveraging recent insights into the function of enhancers, we developed synthetic super-enhancers (SSEs) by assembling functionally validated enhancer fragments into multipart arrays. Focusing on the core SOX2-driven and SOX9-driven transcriptional regulatory network in glioblastoma stem cells (GSCs)1, we engineered SSEs with robust activity and high selectivity. Single-cell profiling, biochemical analyses and genome-binding data indicated that SSEs integrate neurodevelopmental and signalling-state transcription factors to trigger the formation of large multimeric complexes of transcription factors. Moreover, GSC-selective expression of a combination of cytotoxic (HSV-TK and ganciclovir) and immunomodulatory (IL-12) payloads, delivered using adeno-associated virus vectors, as a single treatment led to curative outcomes in a mouse model of aggressive glioblastoma. Notably, IL-12 induced an immunological memory that prevented tumour recurrence. The activity and selectivity of the adeno-associated virus and SSE were validated using primary human glioblastoma tissue and normal cortex samples. In summary, SSEs harness the unique core transcriptional programs that define the GSC phenotype and enable precision immune activation. This approach may have broader applications in other contexts when precise control of transgene expression in specific cell states is necessary.

DOI: 10.1038/s41586-026-10329-6

Source: https://www.nature.com/articles/s41586-026-10329-6