Daniela Gaebler Stephanie J. Hachey Christopher C. Hughes ^*

• University of California, Irvine, Irvine, United States

The tumor microenvironment (TME) comprises a diverse array of cells, both cancerous and non-cancerous, including stromal cells and immune cells. Complex cellular interactions among these cells play a central role in driving cancer progression, impacting critical aspects such as tumor initiation, growth, invasion, response to therapy, and the development of drug resistance.While targeting the TME has emerged as a promising therapeutic strategy, there is a critical need for innovative approaches that accurately replicate its complex cellular and non-cellular interactions;the goal being to develop targeted, personalized therapies that can effectively elicit anti-cancer responses in patients. Microfluidic systems present notable advantages over conventional in vitro 2D co-culture models and in vivo animal models, as they more accurately mimic crucial features of the TME and enable precise, controlled examination of the dynamic interactions among multiple human cell types at any time point. Combining these models with next-generation technologies, such as bioprinting, single cell sequencing and real-time biosensing, is a crucial next step in the advancement of microfluidic models. This review aims to emphasize the importance of this integrated approach to further our understanding of the TME by showcasing current microfluidic model systems that integrate next-generation technologies to dissect cellular intra-tumoral interactions across different tumor types. Carefully unraveling the complexity of the TME by leveraging next generation technologies will be pivotal for developing targeted therapies that can effectively enhance robust anti-tumoral responses in patients and address the limitations of current treatment modalities.