Bioprinted Fibroblast Mediated Heterogeneous Tumor Microenvironment for Studying Tumor‐Stroma Interaction and Drug Screening

Abstract Cancer‐associated fibroblasts (CAFs) are crucial stromal cells in the tumor microenvironment, affecting cancer growth, angiogenesis, and matrix remodeling. Developing an effective in vitro tumor model that accurately recapitulates the dynamic interplay between tumor and stromal cells remains a challenge. In this study, a 3D bioprinted fibroblast ‐ mediated heterogeneous breast tumor model was created, with tumor cells and fibroblasts in a bionic matrix. The impact of transforming growth factor‐β （TGF‐β） on the dynamic transformation of normal fibroblasts into CAFs and its subsequent influence on tumor cells is further investigated. These findings reveales a profound correlation between CAFs and several critical biological processes, including epithelial‐mesenchymal transition (EMT), extracellular matrix (ECM) remodeling, gene expression profiles, and tumor progression. Furthermore, tumor models incorporating CAFs exhibits reduced drug sensitivity compared to models containing tumor cells alone or models co‐cultured with normal fibroblasts. These results underscore the potential of the in vitro fibroblast‐mediated heterogeneous tumor model to simulate real‐life physiological conditions, thereby offering a more effective drug screening platform for elucidating tumor pathogenesis and facilitating drug design prior to animal and clinical trials. This model's establishment promotes the understanding of tumor‐stromal interactions and their therapeutic implications.