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To fulfill such potential, it is crucial that 3D tumor testing platforms completely emulate in vitro the complex in vivo tumor niche and its cellular constituents. Mesenchymal stem cells (MSCs) are recognized to play a pivotal multi\u2010modulatory role in cancer, generating interest as biological targets and as key tumor suppressing, or tumor promoting effectors. This review discusses the biological influence of different types of MSCs in the tumor microenvironment and showcases recent studies that engineer 3D MSCs\u2010cancer cells co\u2010cultures as advanced in vitro therapy testing platforms. A special focus is given to MSCs\u2010cancer 3D co\u2010culture set\u2010up parameters, challenges, and future opportunities. 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