Engineering editopes through programmable RNA editing toward tumor neoantigen generation
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.
Authors
- Rienk Offringa (ORCID: https://orcid.org/0000-0001-6310-1026)
- John M. Lindner (ORCID: https://orcid.org/0000-0002-4940-5354)
- Riccardo Pecori (ORCID: https://orcid.org/0000-0001-9052-4075)
- Mohammad Abukhalaf (ORCID: https://orcid.org/0000-0003-4536-7036)
- Rona Merdler-Rabinowicz (ORCID: https://orcid.org/0000-0002-6133-8158)
- Khwab Sanghvi (ORCID: https://orcid.org/0000-0002-0958-1433)
- Beatrice Casati (ORCID: https://orcid.org/0000-0001-8516-5792)
- Stefan Tenzer (ORCID: https://orcid.org/0000-0003-3034-0017)
- Veronica Pinamonti (ORCID: https://orcid.org/0000-0001-5253-095X)
- David Gómez-Zepeda (ORCID: https://orcid.org/0000-0002-9467-1213)
- Eytan Ruppin (ORCID: https://orcid.org/0000-0002-7862-3940)
- Stefan Zens (ORCID: https://orcid.org/0000-0003-0538-9652)
- Erez Y. Levanon (ORCID: https://orcid.org/0000-0002-3641-4198)
- F. Nina Papavasiliou (ORCID: https://orcid.org/0000-0002-5971-7909)
- Rafael Carretero (ORCID: https://orcid.org/0000-0002-5988-829X)
- Annette Arnold
- Netanel Landesman
- Kai Kipfstuhl
- Mantiana Topouzi
- Michael Platten
- Ece Bilgin (ORCID: https://orcid.org/0009-0005-8976-2929)
Institutions
- Bar-Ilan University (IL)
- Universidad de Granada (ES)
- German Cancer Research Center (DE)
- Johannes Gutenberg University Mainz (DE)
- Heidelberg University (DE)
- University Hospital Heidelberg (DE)
- University Medical Center of the Johannes Gutenberg University Mainz (DE)
- Helmholtz Institute Mainz (DE)
- National Cancer Institute (US)
- University Medical Centre Mannheim (DE)
- BioMed X Institute (DE)
Publication Details
- Journal
- The EMBO Journal
- Published
- 2026-08-14
- DOI
- https://doi.org/10.1038/s44318-026-00870-5
- Primary Topic
- RNA regulation and disease
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Deutsches Krebsforschungszentrum
- Deutsche Forschungsgemeinschaft
- Israel Science Foundation
- Helmholtz Association