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| Home > Publications database > Engineering editopes through programmable RNA editing toward tumor neoantigen generation. |
| Home > Publications database > Engineering editopes through programmable RNA editing toward tumor neoantigen generation. |
| Journal Article | DKFZ-2026-02031 |
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2026
Nature Publishing Group UK
[London]
Abstract: Neoepitope-based therapies hold great promise for cancer immunotherapy because they target tumor-specific mutations and elicit potent anti-tumor T-cell responses. However, their clinical implementation remains limited by the complexity of neoepitope discovery and uncertainty regarding presentation by tumor cells. A potential alternative is the generation of immunogenic neoepitopes directly within cancer cells through programmable RNA editing. Here, we develop Short Precise-Encodable ADAR Recruiting (SPEAR) gRNAs that harness endogenous ADAR1 to direct precise adenosine-to-inosine (A-to-I) editing at selected transcript sites. Using these gRNAs, we demonstrate the generation of immunogenic neoepitopes through RNA editing at the transcript level, termed editopes. In a proof-of-concept model based on the melanoma antigen MART-1, SPEAR-mediated RNA editing restored antigen-specific T cell recognition and enabled tumor control in vivo. Finally, we developed a computational pipeline to identify candidate tumor-selective neoepitopes across multiple cancer types amenable to guided RNA editing. Our findings establish programmable RNA editing as a strategy for engineering immunogenic editopes and provide a framework for neoepitope-directed cancer immunotherapy.
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