171038 20260505142649.0 doi 10.1016/j.ccell.2026.02.013 sideral 149120 ART-2026-149120 eng Marco, Sonia Radiotherapy synergizes with an inducible AAV-based immunotherapy platform to program local and systemic antitumor immunity 2026 Radiotherapy (RT) can prime the immune system against cancer but often fails to generate effective antitumor responses due to concomitant induction of immunosuppressive factors. To overcome this limitation, we built upon the observation that RT enhances adeno-associated vectors (AAVs) tumor transduction through the epigenetic modification of vector episomes. We designed an AAV-based platform to deliver immunostimulatory cytokines through an interferon (IFN)-inducible promoter that allows for spatial control of transgene expression into irradiated tumors. As opposed to a constitutive system, local delivery of a vector encoding for inducible IL-12 (AAV-iIL12) achieves an efficient production of the cytokine without significant toxicity. Combination of RT and AAV-iIL12 generates a highly immunostimulatory tumor microenvironment (TME) leading to robust local and systemic antitumor responses in an IFNγ- and FAS-dependent manner, able to overcome common immune-evasion mechanisms. Our work shows that radiation coupled with AAV-based immune-gene delivery is an efficient and safe approach to treat cancer. Access copy available to the general public Unrestricted info:eu-repo/grantAgreement/ES/DGA/B29-20R info:eu-repo/grantAgreement/ES/ISCIII/CB21-13-00087 info:eu-repo/grantAgreement/ES/MCIU-AEI/PID2020-113963RB-I00 Desasignar info:eu-repo/grantAgreement/ES/MCIU/PID2024-160227OB-I00 info:eu-repo/semantics/openAccess by-nc https://creativecommons.org/licenses/by-nc/4.0/deed.es info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion Fernández, Myriam Honorato, Beatriz Juanarena, Nerea Sainz, Cristina Andueza, Ainhoa Gould, David J. Anderson, Seth de Andrea, Carlos Domínguez, Paulo Pérez Wong, Paolo Vásquez, Carlos Narinda, Irene Unzu, Carmen Isola, Sergio Tavira, Beatriz Ariz, Mikel Camps, Gracián Sanmamed, Miguel F. Pardo, Julián Universidad de Zaragoza (orcid)0000-0003-0154-0730 Labiano, Sara Alonso, Marta M. Marco-Sanz, Javier Guruceaga, Elizabeth Collantes, María Simón, Jon Ander Peñuelas, Iván Fernández-Irigoyen, Joaquín Santamaría, Enrique Prieto, Jesús Dubrot, Juan 1011 566 Universidad de Zaragoza Dpto. Microb.Ped.Radio.Sal.Pú. Área Inmunología 44 (2026), 17 pp. CANCER CELL CANCER CELL 1535-6108 16131738 http://zaguan.unizar.es/record/171038/files/texto_completo.pdf Versión publicada 1781663 http://zaguan.unizar.es/record/171038/files/texto_completo.jpg?subformat=icon icon Versión publicada oai:zaguan.unizar.es:171038 articulos driver 2026-05-05-13:36:17 ARTICLE