Patient-derived organoids in pancreatic cancer: Advances and applications in precision oncology

Abstract

Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest malignancies owing to late diagnosis, extensive intratumoral heterogeneity, a dense desmoplastic tumor microenvironment, and limited therapeutic responsiveness. Although current treatment regimens, including FOLFIRINOX and gemcitabine plus nab-paclitaxel, have modestly improved survival, chemoresistance and the lack of reliable predictive biomarkers continue to hinder precision oncology. Conventional two-dimensional cell lines and many in vivo models do not fully recapitulate the complex architecture, cellular interactions, and biological heterogeneity of human PDAC. Patient-derived organoids (PDOs) have emerged as physiologically relevant three-dimensional models that preserve the genetic, molecular, and phenotypic characteristics of the original tumor while enabling rapid ex vivo pharmacotyping and functional therapeutic evaluation. This review summarizes recent advances in PDAC organoid technology, including tissue acquisition, organoid establishment, molecular characterization, biobanking, and integration with cancer-associated fibroblasts, immune cells, endothelial cells, CRISPR/Cas9 genome editing, assembloid systems, and microfluidic organ-on-chip platforms. We further discuss the applications of PDOs in drug screening, molecular subtype characterization, modeling therapeutic resistance, and supporting precision treatment strategies, together with emerging evidence from prospective clinical studies. Finally, we critically examine the remaining translational challenges, including culture-induced phenotypic drift, limited microenvironmental complexity, interlaboratory variability, assay standardization, and regulatory implementation. Although PDOs represent promising platforms for functional precision oncology, widespread clinical adoption will require standardized methodologies, prospective multicenter validation, and regulatory qualification before routine integration into clinical decision-making.