Exploring the landscape of current in vitro and in vivo models and their relevance for targeted radionuclide theranostics

Abstract Cancer remains a leading cause of mortality globally, driving ongoing research into innovative treatment strategies. Preclinical research forms the base for developing these novel treatments, using both in vitro and in vivo model systems that are, ideally, as clinically representative as possible. Emerging as a promising approach for cancer management, targeted radionuclide theranostics (TRT) uses radiotracers to deliver (cytotoxic) radionuclides specifically to cancer cells. Since the field is relatively new, more advanced preclinical models are not yet regularly applied in TRT research. This narrative review examines the currently applied in vitro, ex vivo and in vivo models for oncological research, discusses if and how these models are now applied for TRT studies, and whether not yet applied models can be of benefit for the field. A selection of different models is discussed, ranging from in vitro two-dimensional (2D) and three-dimensional (3D) cell models, including spheroids, organoids and tissue slice cultures, to in vivo mouse cancer models, such as cellline-derived models, patient-derived xenograft models and humanized models. Each of the models has advantages and limitations for studying human cancer biology, radiopharmaceutical assessment and treatment efficacy. Overall, there is a need to apply more advanced models in TRT research that better address specific TRT phenomena, such as crossfire and abscopal effects, to enhance the clinical relevance and effectiveness of preclinical TRT evaluations.