文章：

合成超级增强子实现精准病毒免疫治疗

Synthetic super-enhancers enable precision viral immunotherapy

原文发布日期：2026-04-08

DOI: 10.1038/s41586-026-10329-6

类型: Article

开放获取: 是

英文摘要：

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.

摘要翻译： 

细胞类型特异性启动子在基因治疗中用于限制治疗载荷的表达。然而，这些启动子往往在强度、选择性和大小方面存在不足。在此，我们利用对增强子功能的最新认识，通过将功能验证的增强子片段组装成多段阵列，开发了合成超级增强子（SSE）。聚焦于胶质母细胞瘤干细胞（GSC）中SOX2和SOX9驱动的核心转录调控网络，我们设计出具有强大活性和高选择性的SSE。单细胞分析、生物化学检测及基因组结合数据表明，SSE整合了神经发育和信号状态相关的转录因子，从而触发形成大的转录因子多聚复合物。此外，使用腺相关病毒载体递送细胞毒性（HSV-TK/更昔洛韦）和免疫调节（IL-12）组合载荷，在侵袭性胶质母细胞瘤小鼠模型中单次治疗即可实现治愈效果。值得注意的是，IL-12诱导了免疫记忆，防止肿瘤复发。通过原代人胶质母细胞瘤组织和正常皮层样本验证了腺相关病毒及SSE的活性和选择性。总之，SSE利用了定义GSC表型的独特核心转录程序，实现了精准的免疫激活。该方法在需要对特定细胞状态中的转基因表达进行精确调控的其他情境下，可能具有更广泛的应用前景。

原文链接：

Synthetic super-enhancers enable precision viral immunotherapy