Engineering editopes through programmable RNA editing toward tumor neoantigen generation: method
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 b...
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| Auteurs principaux: | , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article (Journal) |
| Langue: | anglais |
| Publié: |
2026
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| In: |
The EMBO journal
Year: 2026, Pages: 1-24 |
| ISSN: | 1460-2075 |
| DOI: | 10.1038/s44318-026-00870-5 |
| Accès en ligne: | Verlag, kostenfrei, Volltext: https://doi.org/10.1038/s44318-026-00870-5
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| Notes sur l'auteur: | Riccardo Pecori, Beatrice Casati, Rona Merdler-Rabinowicz, Netanel Landesman, Khwab Sanghvi, Stefan Zens, Ece Bilgin, Mantiana Topouzi, Kai Kipfstuhl, Veronica Pinamonti, Annette Arnold, Mohammad Abukhalaf, David Gomez-Zepeda, Stefan Tenzer, John M. Lindner, Michael Platten, Rienk Offringa, Rafael Carretero, Eytan Ruppin, Erez Y. Levanon & Fotini Nina Papavasiliou |
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| 245 | 1 | 0 | |a Engineering editopes through programmable RNA editing toward tumor neoantigen generation |b method |c Riccardo Pecori, Beatrice Casati, Rona Merdler-Rabinowicz, Netanel Landesman, Khwab Sanghvi, Stefan Zens, Ece Bilgin, Mantiana Topouzi, Kai Kipfstuhl, Veronica Pinamonti, Annette Arnold, Mohammad Abukhalaf, David Gomez-Zepeda, Stefan Tenzer, John M. Lindner, Michael Platten, Rienk Offringa, Rafael Carretero, Eytan Ruppin, Erez Y. Levanon & Fotini Nina Papavasiliou |
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| 520 | |a 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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