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Background The emergence of cell and gene therapies (CGTs) and biologics calls for precise preclinical approaches capable of generating robust and translatable data. To address this need, we introduce a flexible design framework tailored for oncology drug development, using immunodeficient, immunocompetent, and humanized immune system mice. This framework allows researchers to align preclinical study design with the unique features of each therapeutic candidate.Methods The framework is structured around the rational selection of critical parameters: tumor type, biomarker expression, engraftment site, immune system status, as well as clinical, cellular, and molecular readouts. It guides users in designing studies that can yield meaningful data across multiple specific aims, including the assessment of immune cell persistence, biodistribution, safety, efficacy, and mechanism of action.Results Through illustrative case studies, we highlight successful applications of this approach across diverse CGTs—including CAR-T, CAR-NK, TCR-T cells, and extracellular vesicles—in both autologous and allogeneic settings. By leveraging the growing accessibility of customizable mouse models and robust immunological assays, this modular approach improves study relevance and reliability.Conclusions Beyond oncology, the flexibility of this framework allows it to be extended to other immune-related areas such as infectious or inflammatory diseases. Overall, it offers a practical roadmap to enhance predictiveness, reduce attrition, and accelerate the translation of next-generation therapeutics.Ethics Approval This work does not involve human subject research. Animal experimentation procedures have been approved by the French Ministry of Higher Education and Research (DAP authorization 38383 – 2022082413416895) and the Departmental Directorate of Population Protection in Haute Savoie, France (DDPP authorization A 7418 324). TransCure bioServices is an an AAALAC-accredited institution.