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

## TL;DR

This review highlights a lack of reliable models for most peripheral T-cell lymphomas, emphasizing the need for advanced preclinical platforms to improve research and drug development.

## Contribution

The paper identifies a critical gap in preclinical models for PTCLs and advocates for the adoption of patient-derived and 3D models to better reflect tumor biology.

## Key findings

- Current preclinical models are heavily skewed toward T-ALL, CTCL, and ALCL, with few models for PTCL subtypes.
- Advanced models like PDX and 3D cultures better capture tumor heterogeneity and microenvironmental context.
- The lack of PTCL models hinders mechanistic studies and therapeutic progress in these aggressive lymphomas.

## Abstract

What are the main findings?
This review maps the current preclinical landscape of T-cell malignancies, showing a marked excess of T-ALL, CTCL, and ALCL cell lines contrasted with a near-complete lack of reliable models for most peripheral T-cell lymphoma (PTCL) entities.It delineates how newer platforms—such as patient-derived xenografts, 3D cultures, and “avatar” models—better recapitulate tumor biology and microenvironmental dependence than conventional 2D cell lines.

This review maps the current preclinical landscape of T-cell malignancies, showing a marked excess of T-ALL, CTCL, and ALCL cell lines contrasted with a near-complete lack of reliable models for most peripheral T-cell lymphoma (PTCL) entities.

It delineates how newer platforms—such as patient-derived xenografts, 3D cultures, and “avatar” models—better recapitulate tumor biology and microenvironmental dependence than conventional 2D cell lines.

What is the implication of the main finding?
The imbalance in available models helps explain why research and drug development are concentrated in a few T-cell lymphoma subtypes, underscoring the need for coordinated efforts to establish, authenticate, and share models of rare PTCLs.Integrating advanced, patient-tailored models into preclinical pipelines may improve target discovery, refine drug sensitivity testing, and ultimately support more effective precision medicine strategies in T-cell malignancies.

The imbalance in available models helps explain why research and drug development are concentrated in a few T-cell lymphoma subtypes, underscoring the need for coordinated efforts to establish, authenticate, and share models of rare PTCLs.

Integrating advanced, patient-tailored models into preclinical pipelines may improve target discovery, refine drug sensitivity testing, and ultimately support more effective precision medicine strategies in T-cell malignancies.

T-cell malignancies represent a complex spectrum of clinically and biologically heterogeneous diseases. Effective translational research and drug development are critically dependent on preclinical models that faithfully recapitulate this diversity. This review analyzes the current preclinical landscape, identifying a profound disparity between the clinical 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 selection 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 xenografts (PDX) and 3D organoid systems. These “avatar” models preserve vital tumor heterogeneity and microenvironmental context, offering superior predictive value. The systematic 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.