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Background The development of therapeutic antibodies—designed to enhance specificity and harness the patient’s own immune system against disease—is hampered by a high rate of clinical trial failure, highlighting a critical need for more predictive preclinical models. Humanized mouse models, which support the development of functional human immune compartments, offer a promising solution to bridge this translational gap.Methods We introduce here a modular strategy for the rational design of preclinical studies in oncology. The foundation of this approach is the selection of a mouse model reconstituted with a complete human immune system via transplantation of CD34+ hematopoietic stem cells (HSCs) into immunodeficient strains. This process enables the development of human T, B, NK, and myeloid cells, which can be further expanded using cytokine boosting with hydrodynamic gene delivery.Results The choice of humanizable mouse strain (e.g. NSG, NCG, NOG-EXL, NCG-X) is based on immune reconstitution profile and kinetics post-HSC engraftment, thereby optimizing experimental conditions to address specific study aims. Building on this foundational model, additional study components include the type of tumor (e.g. lung, breast, melanoma, ovarian, pancreatic), anatomical site of engraftment (orthotopic or subcutaneous), and a diverse array of analytical endpoints including flow cytometry, immunohistochemistry, qPCR, ELISA, and ELISpot. We illustrate the utility of this framework through several case examples evaluating the pharmacodynamics, safety, efficacy, and mechanisms of action of therapeutic antibodies—both approved and investigational. These include immune checkpoint inhibitors (PD-1, PD-L1, OX40), bispecific T engagers (CD3xCD20 or CD3xEGFR), and tumor-specific antibodies (EGFR, Her2, CD47), tested across various tumor contexts.Conclusions This modular and adaptable framework underscores the value of humanized mouse models for robust, mechanism-driven assessment of immunotherapies, offering potential not only across oncological indications but also in broader immune-mediated disease settings.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 autorization A 7418 324). TransCure bioServices is an an AAALAC-accredited institution.