Alessandra GhigoPietro AmeriAarti AsnaniEdoardo BerteroRudolf A. de BoerDimitrios FarmakisArantxa GonzálezStephane HeymansBorja IbáñezTeresa López‐FernándezAlexander R. LyonPiero PolleselloAmina RakishevaKonstantinos StellosKatrin Streckfuss‐BömekeCarlo Gabriele TocchettiThomas ThumPeter van der MeerEva Van RooijPiotr PonikowskiMarco MetraGiuseppe RosanoSophie Van Linthout2025-03-202025-03-202025-03-11Eur J Heart Fail. 2025 Mar.1388-98421879-0844https://hdl.handle.net/20.500.12105/26539A.G. was supported by grants from the Italian Ministry of Health (GR-2021-12371950) and the Italian Ministry of Education, Universities and Research (PRIN 2022 20223YPL49; PRIN PNRR 2022 P2022ZB72T). P.A. was supported by PNRR-MAD-2022-12376632 (CUP C63C22001360006) funded by the European Union - Next Generation EU - NRRP M6C2 - Investment 2.1 Enhancement and strengthening of biomedical research in the NHS. A.A. is supported by NIH R01HL163172, R01HL166541, and R01HL157530; a sponsored research agreement with Genentech; and a HESI Thrive Award. R.A.d.B. is supported by the Netherlands Heart Foundation (grants 2020B005 and 01–003–2022-0358) and by the European Research Council (ERC CoG 818715). A.Go. was supported by the Spanish Ministry of Science, Innovation and Universities (Instituto de Salud Carlos III: CB16/11/00483 and PI21/00946 co-financed with ERDF funds and CIBERCV InCare project). B.I. is supported by grants from the European Commission (ERC-CoG 819775 and H2020-HEALTH 945118), the Spanish Ministry of Science and Innovation (PID2022-140176OB-I00), La Caixa Foundation (HR22-00533), and the Red Madrileña de Nanomedicina en Imagen Molecular -Comunidad de Madrid (P2022/BMD-7403 RENIM-CM). A.R.L. is supported by the Fondation Leducq Network of Excellence in Cardio-Oncology, the Royal Brompton Cardio-Oncology Centre of Excellence and The Big Heart Foundation. K.S. is supported by grants from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (MODVASC, grant agreement No 759248), the German Research Foundation DFG (CRC1366 C07, project number 394046768), the Health+Life Science Alliance Heidelberg Mannheim GmbH and the Biotechnology and Biological Sciences Research Council (BBSRC) of the UK Research and Innovation (UKRI). K.S.B. is supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation, Project 471241922, CRC1213-B07 and the research training group RTG2824). C.G.T. is supported by the Italian Ministry of Health (PNRR-MAD-2022-12376632 and RF-2016-02362988). T.T. was supported by the ERC Advanced Grant REVERSE and the Deutsche Forschungsgemeinschaft (CRC1470). P.v.d.M. is supported by a grant from the European Research Council (ERC CoG 101045236, DISSECT-HF). S.V.L. is supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation, CRC-1470-A07 and Project 536819681) and the Deutsche Krebshilfe (Project 70115119).New anticancer therapies with potential cardiovascular side effects are continuously being introduced into clinical practice, with new and often unexpected toxicities becoming apparent only after clinical introduction. These unknown toxicities should be identified and understood beforehand to better prepare patients and physicians, enabling the implementation of effective treatments. Therefore, there is a crucial need for appropriate preclinical models to understand the biological basis of their cardiotoxicity. This scientific statement summarizes the preclinical models hitherto used, from in vitro two- and three-dimensional human systems to small and large animals, to pinpoint the molecular mechanisms behind the cardiotoxicity of new-generation anticancer therapies, particularly immunotherapies, and to develop potential cardioprotective strategies. Furthermore, it discusses how preclinical models have contributed to the provocative concept of heart failure being potentially tumorigenic and how the discovery of drugs with both anticancer and cardioprotective actions has revealed a common mechanistic basis for heart failure and cancer. Finally, it discusses the existing gaps between preclinical models and clinical observations in patients, how these discrepancies affect regulatory pathways and the drug development process in cardio-oncology and provides recommendations for closing these gaps.engVoRhttp://creativecommons.org/licenses/by/4.0/Attribution 4.0 International10.1002/ejhf.3636European journal of Heart Failureopen access