Salivary gland tumor organoids: from biological fidelity to biomarker discovery and precision oncology

Salivary gland tumors (SGTs) are rare, histologically diverse neoplasms for which diagnostic complexity, limited access to representative experimental models, and marked interpatient variation in treatment response remain major challenges. Patient-derived organoids (PDOs) provide three-dimensional culture systems that can preserve selected architectural, phenotypic, and molecular features of the parental tumor while enabling expansion, controlled perturbation, and functional testing. This review critically examines the development of SGT organoid models and their applications in disease modeling, biomarker discovery, and precision oncology. Current evidence indicates that SGT organoids can retain subtype-associated morphology, lineage markers, driver alterations, fusion genes, transcriptomic programs, and interpatient heterogeneity. Multi-subtype biobanks have enabled the identification of candidate diagnostic biomarkers, including PTP4A1 in mucoepidermoid carcinoma and EN1 in adenoid cystic carcinoma. Genotype-informed and phenotype-based screening has also generated preclinical evidence for targeted therapy in adenoid cystic carcinoma and salivary duct carcinoma. However, establishment efficiency varies substantially among cohorts and cannot be compared without accounting for specimen composition, culture conditions, passage requirements, and definitions of successful establishment. Culture-associated epithelial selection, loss of diagnostically or therapeutically relevant proteins, and incomplete representation of immune and stromal compartments can further dissociate genomic fidelity from phenotypic and pharmacological fidelity. Clinical translation will therefore require standardized reporting, longitudinal quality control, reconstruction of disease-relevant microenvironmental components, matched normal-tissue controls for toxicity assessment, and prospective validation against patient outcomes. At present, SGT organoids are best considered patient-derived experimental models that complement pathology, molecular profiling, and in vivo systems.