Advancing neurofibromatosis research: a comparative review of animal models and their utility in dissecting the tumor microenvironment.

Neurofibromatosis is a genetic disorder characterized by nervous system tumors arising primarily from NF1 or NF2 mutations. Given the complexity of the genetic background and heterogeneity of associated tumor phenotypes in neurofibromatosis, mechanistic investigations rely heavily on experimental animal models. Human tissue-based studies alone cannot fully elucidate causal relationships, temporal dynamics, modifier gene effects, or cell type-specific contributions to tumor development, progression, and microenvironmental regulation. Consequently, various animal models have been developed, including genetically engineered mouse models, large-animal systems, alternative vertebrate models, and transplantation-based approaches. These experimental platforms enable the controlled manipulation of gene dosage, lineage-specific gene deletion, immune modulation, targeted disruption of stromal and extracellular matrix components, and evaluation of therapeutic response and drug resistance mechanisms. Animal models have helped demonstrate the cell-autonomous and non-cell-autonomous mechanisms underlying neurofibromatosis tumorigenesis. Furthermore, sustained tumor maintenance and progression require coordinated interactions between neoplastic cells and their surrounding microenvironment. Notably, these experimental systems offer a temporal resolution not achievable in clinical specimens, demonstrating that microenvironmental alterations may precede overt tumor formation. Such findings depict the tumor microenvironment (TME) as an active contributor to disease rather than merely as a consequence of tumor growth. In this review, we evaluate the experimental scope, methodological strengths, and inherent limitations of current animal models used in neurofibromatosis research, with emphasis on their utility in elucidating interactions within the TME and non-neoplastic disease manifestations. This work characterizes model-specific advantages and constraints to emphasize the continued importance of animal models as essential tools for hypothesis-driven investigation and translational development in elucidating the various attributes of neurofibromatosis.