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The tumor microenvironment (TME) is a complex and dynamic system that plays a crucial role in tumor progression, immune evasion, and therapy resistance. The TME is composed of various cell types, including tumor cells, stromal cells, and immune cells, such as macrophages. Macrophages are versatile myeloid cells that can exhibit both protumoral and anti-tumoral functions, depending on their phenotype and the TME context. Classically activated M1 macrophages exhibit proinflammatory and tumoricidal functions and have demonstrated promising anti-tumor effects in immunotherapy research. Conversely, alternatively activated M2 macrophages have wide ranging functions in tissue repair and immune regulation. Tumor associated M2 macrophages (TAMs) are common in the TME where they play a strong anti-inflammatory role and promote tumor immune escape. Understanding the complex interactions between macrophages and the TME is, therefore, essential for developing effective anti-cancer immunotherapies.

The development of immunotherapies typically involves using both in vitro and in vivo tumor models. Classical in vitro 2D models are relatively fast and inexpensive but lack the spatial complexity and heterogeneity of the TME. In vivo mouse models provide a more physiologically relevant system for evaluating the effectiveness of therapies; however, they are time consuming, expensive, and present some significant limitations. Human xenograft models require immunocompromised or humanized mice deficient in several cell types so fail to accurately recreate the TME. 3D bioprinting technology offers a novel approach for creating biomimetic in vitro models of tumors and the TME. By combining the fields of engineering, materials science, and cell biology, 3D bioprinting allows for the rapid and cost-effective creation of complex tissue constructs that accurately mimic the architecture and composition of native tissues. Our research is currently focused on using this technology to recreate the TME by incorporating myeloid, stomal, and tumor cells into 3D bioprinted structures. Utilizing these models, we will investigate the signals which drive the formation of the TME and gain insight on the functions of suppressor cells such as TAMs. Additionally, these models will aid in the development of novel anti-cancer immunotherapies able to evade or repolarize the immunosuppressive TME. We anticipate that our experience creating 3D bioprinted tumor models will facilitate collaborative efforts to screen a wide range of innovative therapies and support translation from bench to bedside.

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3D Bioprinting the Tumor Microenvironment for Immunotherapy Development