Reducing off-target toxicities in cancer gene therapy is essential for its clinical translatability. One method to foster selectivity is to utilize cell type–specific enhancers; however, size, selectivity, strength, and sequence quality impede success. Therefore, Koeber, Matjusaitis, and colleagues engineered synthetic super-enhancers (SSE), capable of driving targeted, strong expression of therapeutic agents in glioblastoma (GBM). To identify glioblastoma stem cell (GSC)-specific enhancer fragment candidates, a functional screen was conducted based on SOX2 binding sites. SSEs were constructed with four-component combinations of top candidates, which demonstrated high, selective activity in GSCs over other cell types. Additionally, multimeric complex formation was seen in GSC cell extracts, but not in differentiated glial cells, indicating not only cell type but also differentiation state–specific activity. Moreover, cooperation between both SOX2 and SOX9 were needed for optimal SSE activity. Analysis of single-cell RNA sequencing data and a kinase inhibitor screen identified several signaling pathways, including the MAPK pathway, as correlated with the activity of a representative candidate, SSE-7. To assess tumor tissue–specific SSE-7 activity, tumor and margin tissue slices from patients with GBM were stained to detect an mCherry reporter and GSC markers, including SOX2. SSE-7 activity was seen in 90% of mCherry-positive tumor cells with SOX2 co-expression, while control CMV expression occurred across normal tissue, indicating tumor-specific activation of SSE-7. In assessing its therapeutic utility, an SSE-7 transgene was constructed with both cytotoxic (HSV-TK) and immunogenic (IL12) payloads and directly injected into tumors using an adeno-associated virus delivery method in a mouse model of GBM. Mice that received the transgene displayed tumor regression and clearance after 3–5 weeks with no tumor regrowth or observed toxicity after 11 months, while control mice died after 1–2 weeks, demonstrating efficacy and a favorable toxicity profile. IL12 induced T helper responses that drove an increase in cytotoxic T cells. Together, these results support SSE-driven expression of therapeutically relevant payloads as a potentially feasible, effective, and safe strategy to selectively kill tumor cells in preclinical models of GBM.Koeber U, Matjusaitis M, Alfazema N, Furlong K, Wang Z, White R, et al. Synthetic super-enhancers enable precision viral immunotherapy. Nature 2026 Apr 8 Epub ahead of print.Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at https://aacrjournals.org/cdnews.
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