Rebuilding the Marrow In Vitro: Translational Advances in the 3D Modeling of Blood Cancers

Hematological malignancies such as acute myeloid leukemia (AML), chronic myeloid leukemia (CML), lymphomas, and multiple myeloma remain difficult to model ex vivo because conventional two-dimensional (2D) cultures and murine systems fail to reproduce the spatial, metabolic, vascular, and immune complexity of human bone marrow and lymphoid niches. Recent advances in three-dimensional (3D) platforms—including spheroids, engineered organoid-like marrow models, and microfluidic niche-on-a-chip systems—now allow for a more physiological replication of stromal, endothelial, and immune interactions that drive resistance and relapse. In this review, we introduce explicit definitions distinguishing spheroids, organoid-like constructs, true hematopoietic organoids, and microfluidic devices to establish a unified framework for hematologic 3D modeling. We synthesize applications across AML, CML, lymphoma, and myeloma, highlighting mechanistic insights, strengths, and limitations unique to each disease. Finally, we outline a translational roadmap that integrates bioprinting, perfusable vasculature, immune reconstitution, and AI-driven analytics toward next-generation patient-specific platforms. These innovations position 3D marrow-mimetic systems as essential tools for precision oncology in blood cancers.