Next-generation models for lymphoid malignancies: the rise of 3D culture systems in translational hematology

Traditional models used to study lymphoid malignancies, such as 2D cell cultures and murine systems, have significantly advanced our understanding of tumour biology and drug development. However, their limited capacity to recapitulate the tumour microenvironment and 3D anatomical structure restricts their translational relevance. In response to these challenges, three-dimensional (3D) culture systems have recently emerged as promising platforms to more accurately replicate the architecture and biological complexity of lymphoid tissues. A variety of 3D models have been developed, ranging from simple spheroids to advanced organ-on-chip technologies that allow for continuous perfusion and precise modulation of microenvironmental parameters. Current optimisation efforts aim to enhance these systems' ability to sustain lymphoma cell viability and mimic key in vivo features such as stromal integration, spatial organisation, and biomechanical cues. This review provides an overview of the current 3D models used to investigate mature lymphoid malignancies, with a particular focus on chronic lymphocytic leukaemia and lymphomas. We discuss their relevance, strengths, and limitations, especially in the context of therapeutic screening and the advancement of personalised treatment approaches.