Cancer-Associated Fibroblasts and Epithelial–Mesenchymal Transition as Critical Contributors to Renal Cell Carcinoma Progression

Renal cell carcinoma (RCC) features a complex tumor microenvironment, where cancer-associated fibroblasts (CAFs) play key roles in tumor progression, epithelial–mesenchymal transition (EMT), immune evasion, and resistance to treatment. This article updates our understanding of CAF origins, diversity, and functions in RCC, incorporating recent single-cell RNA sequencing (scRNA-seq) data that refine CAF subtypes. The paper explores the mechanistic interactions between CAFs and EMT, focusing on CAF-derived signaling pathways like TGF-β, IL-6/STAT3, HGF/c-MET, and Wnt/β-catenin, as well as extracellular-vesicle-mediated transfer of miRNAs and lncRNAs that promote metastatic behavior in RCC. It also addresses how CAF-driven remodeling of the extracellular matrix, metabolic changes, and activation of YAP/TAZ contribute to invasion and resistance to therapies, particularly in relation to tyrosine kinase inhibitors, mTOR inhibitors, and immune checkpoint blockade. The review highlights emerging therapeutic strategies targeting CAFs, such as inhibiting specific signaling pathways, disrupting CAF–tumor cell communication, and selectively depleting CAFs. In conclusion, it identifies limitations in current CAF classification systems and proposes future research avenues to improve RCC-specific CAF profiling and exploit the CAF–EMT axis for therapeutic gain.