Goodbye flat lymphoma biology.

B-cell lymphomas grow in aggregates, closely interacting with specific physical elements and cellular environments. While 2D culture systems have long been the standard in the field, current methodologies aim to better replicate lymphoma biology and its microenvironment in 3D. Significant progress has been made since the first 3D lymphoma cell line culture was developed in 2012. Subsequent advances in both cell line and patient-derived systems have incorporated key physical and cellular microenvironmental components. This Review compiles the relevant 3D non-Hodgkin lymphoma models available, outlining their main features, strengths, and limitations. Additionally, we highlight the critical gaps that must be addressed to develop robust, multiplexed, patient-derived B-cell lymphoma systems, which can serve as reliable avatars alongside clinical trials and contribute to the principles of the 3Rs in animal research. Impact statement In the last few years new B-cell lymphoma 3D models have emerged, with a special emphasis on patient-derived models. These systems are fundamental tools for precision medicine. This review provides translational researchers and clinician scientists with an excellent overview of these novel tools with their strong and weak points.