From Cell Lines to Avatars: Charting the Future of Preclinical Modeling in T-Cell Malignancies

T-cell malignancies represent a complex spectrum of clinically and biologically heteroge-neous diseases. Effective translational research and drug development are critically de-pendent on preclinical models that faithfully recapitulate this diversity. This review ana-lyzes the current preclinical landscape, identifying a profound disparity between the clin-ical spectrum of T-cell neoplasms and the available in vitro tools. We demonstrate that the existing armamentarium of cell lines is heavily skewed, with an abundance of models for T-cell lymphoblastic leukemia/lymphoma (T-ALL), cutaneous T-cell lymphoma (CTCL), and anaplastic large cell lymphoma (ALCL). This skew is a direct result of a biological se-lection bias, as these entities are often driven by potent, TME-independent oncogenes (e.g., NOTCH1 mutations, NPM1-ALK fusions) conducive to immortalization. Conversely, the majority of peripheral T-cell lymphoma (PTCL) subtypes, which are frequently TME-dependent and clinically aggressive, remain "preclinical orphans" with few or no authenticated models. This "preclinical void" constitutes a major bottleneck, impeding mechanistic studies and therapeutic progress. We discuss the limitations of 2D cultures and highlight the necessity of adopting advanced platforms, such as patient-derived xen-ografts (PDX) and 3D organoid systems. These "avatar" models preserve vital tumor het-erogeneity and microenvironmental context, offering superior predictive value. The sys-tematic development and integration of these next-generation models are essential to bridge the translational gap and advance precision medicine for all patients with T-cell malignancies.