Organoid drug screening in cancer: advances in high-throughput platforms and clinical applications

Patient-derived tumor organoids represent the most physiologically relevant 3-dimensional (3D) cancer models, preserving tumor heterogeneity and native tissue architecture. However, their integration into high-throughput screening (HTS) platforms faces critical obstacles, particularly with automated liquid handling, and inter-organoid variability compromises screening reproducibility essential for drug discovery applications. Here, we review innovative platforms developed to overcome these constraints through diverse technological strategies: extracellular matrix (ECM) non-embedded systems that enhance compatibility with automation, on-chip culture arrays that enable precise geometric control and live imaging, microfluidic-based droplet platforms that achieve exceptional organoid uniformity, micropillar-based systems that reconcile ECM embedding with standardization needs, 3D bioprinting platforms with improved spatial organization capabilities, and integrated tumor microenvironment models incorporating functional immune and stromal components. Clinical validation studies demonstrate impressive predictive accuracy, closely aligned with patient treatment responses. The successful preservation of tumor-infiltrating lymphocytes supports comprehensive immunotherapy screening, including checkpoint inhibitors and bispecific antibodies. Despite these technological advances, challenges such as platform standardization, cost-effectiveness, and incomplete microenvironment recapitulation remain major barriers to widespread clinical adoption. The convergence of artificial intelligence, multi-omics integration, and advanced automation is expected to establish organoid HTS as a cornerstone of precision oncology.