Exosomal noncoding RNAs in renal cell carcinoma: Mechanisms, roles, and therapeutic potential

Exosomes, critical mediators within the tumor microenvironment (TME), facilitate intercellular communication by transferring bioactive molecules, including noncoding RNAs (ncRNAs). These extracellular vesicles, secreted by nearly all cell types and detectable in bodily fluids, selectively encapsulate functional ncRNAs, which play pivotal roles in tumorigenesis, progression, and therapeutic resistance. In renal cell carcinoma (RCC), exosomal ncRNAs have emerged as key regulators driving tumor proliferation, metastasis, and immunosuppression through mechanisms such as activation of the MAPK pathway, promotion of epithelial-mesenchymal transition (EMT), and modulation of immune cell polarization. Notably, exosomal ncRNAs contribute to drug resistance by mediating cross-talk between cancer cells and stromal components, including fibroblasts and tumor-associated macrophages (TAMs). Their inherent stability, conferred by protective lipid bilayers, enhances their potential as non-invasive diagnostic and prognostic biomarkers. Specific ncRNAs, such as miR-210 and circSDHC, exhibit differential expression in RCC patient sera and urine, offering high diagnostic accuracy for early detection and metastasis monitoring. Furthermore, targeting exosomal ncRNA biogenesis or their downstream pathways-via engineered exosomes loaded with therapeutic RNAs or inhibitors-represents a promising strategy to overcome resistance and improve treatment efficacy. This review comprehensively delineates the mechanistic roles of exosomal ncRNAs in RCC pathogenesis, highlights their clinical utility as biomarkers, and explores innovative therapeutic approaches to disrupt ncRNA-mediated oncogenic signaling. Advancing our understanding of exosome-ncRNA dynamics may unlock novel precision therapies for RCC, addressing unmet challenges in current clinical management.