2026-06-08T10:17:30Zhttps://docta.ucm.es/rest/oai/request

oai:docta.ucm.es:20.500.14352/1339542026-03-13T00:49:35Zcom_20.500.14352_14col_20.500.14352_15

Selective genome editing of amplified oncogenes triggers immunogenic cell death and tumor remodeling Nieto Sanchez, A. Roda Navarro, Pedro Rodríguez Perales, Sandra 612.017 CRISPR system Cancer targeted therapy Genome editing Immunogenic Cell Death (ICD) Oncogene amplification Preclinical studies ecDNA Ciencias Biomédicas Inmunología 24 Ciencias de la Vida 2412 Inmunología Financiado con Fondos FEDER Oncogene amplifications fuel some of the most lethal, therapy‑refractory cancers, yet remain clinically untargeted. We report a single‑guide CRISPR/Cas9 strategy that converts the sheer copy‑number excess of oncogene amplicons into an Achilles' heel. A solitary intronic double‑strand break is innocuous in diploid genomes but collapses oncogene amplification‑positive cells across neuroblastoma, small‑cell lung and colorectal carcinoma models, driving > 90% loss of viability, G₂/M blockade and catastrophic DNA‑damage signalling. Amplified‑locus cleavage rewires transcription toward cell death activation, necroptosis and cGAS-STING-mediated immunogenic cell death, enabling dendritic‑cell cross‑priming and T‑cell activation and proliferation. In xenografts, delivery of the intronic sgRNA shrinks tumours by 90%, prolongs survival and remodels the innate tumour microenvironment. Deep sequencing confirms negligible off‑target editing, and combination with doxorubicin achieves supra‑additive killing. These findings establish amplification density, not sequence content, as a tractable, tumour‑exclusive target and unveil a dual‑action platform that is simultaneously cytotoxic and immunostimulatory. Editing of tumor amplifications therefore offers a blueprint for translating copy‑number aberrations into precision genome‑editing therapies for treatment‑resistant cancers. Agencia Estatal de Investigación (España) Instituto de Salud Carlos III (España) Depto. de Inmunología, Oftalmología y ORL Fac. de Medicina TRUE pub 2026-03-12T07:19:22Z 2026-03-12T07:19:22Z 2025-12-25 review article VoR https://hdl.handle.net/20.500.14352/133954 1476-4598 10.1186/s12943-025-02542-0 eng info:eu-repo/grantAgreement/ISCIII/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020 (ISCIII)/PI20%2F01837/ES/USO DEL SISTEMA CRISPR%2FCAS13 PARA EL DIAGNOSTICO E INHIBICION DE ONCOGENES DE FUSION/ PI23/01932 info:eu-repo/grantAgreement/ISCIII/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020 (ISCIII)/PI21%2F01641/ES/DESARROLLO DE APROXIMACIONES DE TERAPIA GENICA LENTIVIRAL Y EDICION GÉNICA PARA EL TRATAMIENTO DE TRANSTORNOS PLAQUETARIOS CONGENITOS/ PID2020-115444GB-I00 Nieto-Sanchez A, Martinez-Lage M, Puig-Serra P, Carpintero S, Alonso-Yanez A, Ojeda-Walczuk P, Ibañez-Navarro M, Pita G, Moya FJ, Moreno C, Martin MC, Alonso R, Nuñez-Torres R, Sanchez-Arevalo Lobo VJ, Alonso-Guirado L, Malats N, Gonzalez-Neira A, Fernandez L, Roda-Navarro P, Torres-Ruiz R, Rodriguez-Perales S. Selective genome editing of amplified oncogenes triggers immunogenic cell death and tumor remodeling. Mol Cancer. 2025 Dec 22;25(1):21. doi: 10.1186/s12943-025-02542-0 Attribution-NonCommercial-NoDerivatives 4.0 International http://creativecommons.org/licenses/by-nc-nd/4.0/ open access application/pdf Springer Nature