Renal cell carcinoma organoids: establishment, applications, and clinical translation—current evidence, technical challenges, and future directions

Renal cell carcinoma (RCC) is characterized by marked histological, molecular, and spatial heterogeneity, which contributes to substantial interpatient variability in responses to targeted therapies, immune checkpoint inhibitors, and combination regimens. Conventional two-dimensional cultures and animal models are limited in their ability to simultaneously recapitulate patient-specific tumor features, maintain biological fidelity, and support experimental throughput. Tumor organoids can be expanded in three-dimensional culture while retaining, to varying degrees, the histological and molecular characteristics of their tumors of origin, thereby providing a complementary platform for RCC disease modeling, investigation of drug resistance mechanisms, and functional drug testing. This review is structured according to the source of evidence and the maturity of clinical translation. We summarize the establishment, culture, and quality assessment of RCC patient-derived organoids, three-dimensional tumor spheroids, stem cell-derived kidney organoids, air–liquid interface cultures, and organ-on-chip models, with particular emphasis on distinguishing direct evidence from RCC organoid studies, mechanistic evidence from non-organoid RCC models, and methodological evidence derived from other cancer types. Current evidence supports the use of RCC organoids for preserving tumor phenotypes, investigating tumor heterogeneity, evaluating responses to targeted therapies, and validating mechanisms of drug resistance. However, clinical translation remains limited by variable model-establishment efficiency and stability, incomplete recapitulation of the tumor microenvironment, and insufficient validation against patient outcomes. Future research should improve model representativeness through multiregional and longitudinal sampling, chemically defined matrices, multicellular co-culture systems, vascularized and microfluidic platforms, automated high-content screening, and single-cell and spatial multi-omics approaches. Analytical validity, clinical validity, and clinical utility should be evaluated as distinct but complementary dimensions of translational performance. At present, RCC organoids are best positioned as tools for mechanistic investigation and adjunctive prioritization of therapeutic options rather than as standalone platforms for treatment decision-making independent of pathological classification, molecular testing, and established clinical guidelines.