Precision Oncology at a Crossroads: How Organoid Platforms Are Reshaping the Field

Tumor heterogeneity and microenvironmental complexity remain fundamental barri-ers to genomics-centered precision oncology, frequently causing discordance between molecular alterations and real-world therapeutic responses. Here, we reviewed pa-tient-derived organoid (PDO) technologies as functional platforms that complement molecular profiling by directly investigating patient-specific sensitivity, resistance, and microenvironment dependent vulnerability. We first summarize why convention-al preclinical systems, two-dimensional cell lines and patient-derived xenografts, are limited by reduced biological fidelity, impractical turnaround time, and scalability for clinical decision support. We then synthesized organoid-based evidence across three representative disease malignancies with distinct precision-medicine bottlenecks. Across these settings, we highlight advances that extend the PDO capability beyond the tumor epithelium alone, including air–liquid interface cultures, immune and stro-mal co-cultures, and microfluidic organoid-on-chip systems, as well as integration with multi-omics and artificial intelligence for scalable analytics. Finally, we discuss the key translational requirements, standardization of culture matrices and assay readouts, quality control, automation to reduce turnaround time, and regulato-ry/ethical frameworks, required to transition organoid-guided testing from proof-of-concept to routine implementation. Collectively, this review reframes organ-oids as functional stratification platforms supporting a conceptual shift from geno-type-guided to response-driven precision oncology.