Physiologically relevant 3D tumor models for therapeutic screening

The heterogeneity of the tumor microenvironment poses a significant challenge to the success of anti-cancer therapeutics. Consequently, there is an urgent need to generate comprehensive data to elucidate the mechanisms underlying tumor resistance and to inform the rational and systematic application of anti-cancer drugs to mitigate drug resistance. In-vitro tumor models based on established cell lines are widely employed in studying the mechanisms of action of drugs; however, these traditional models often fail to accurately recapitulate the complexity of native tumors, particularly in terms of the heterogenous and intricate tumor microenvironment, including cellular composition, intercellular communication, and interactions between cells and extracellular matrix. As a result, preclinical data often diverges from clinical outcomes. In recent years, the emergence of patient-derived three-dimensional (3D) models including spheroids, organoids, tumor-on-a-chip systems, and 3D bioprinting has offered promising alternatives for addressing these limitations and enhancing the predictive power of tumor drug screening. In this review, we explore the relationship between the complexity of the tumor microenvironment, tumor drug resistance, and then introduce the current biofabrication techniques enabling the reconstruction of 3D tumor models in vitro. We delve deeper into a myriad of applications of such models for a wide range of cancer indications. These models offer a morfailures andlly relevant platform for evaluating anti-cancer drugs with the potential to improve translational accuracy, reduce drug development failures, and accelerate the discovery of cancer therapies.