Locally advanced or metastatic renal cell carcinomas (mRCCs) account for up to 15% of all kidney cancer diagnoses. Systemic therapies (with or without surgery) represent gold standard treatments, mostly based on tyrosine kinase inhibitors in association with immunotherapy. We provide an overview of the current knowledge of miRNAs as predictors of treatment resistance. A systematic review of the literature was carried out in January 2022 following the PICO methodology. Overall, we included seven studies—four testing plasmatic miRNAs, two exosomal miRNAs, and one urinary miRNA. A total of 789 patients were included (354 for plasmatic miRNAs, 366 for urinary miRNAs, and 69 for exosomal miRNAs). Several miRNAs were tested within the included studies, but six plasmatic (miR9-5-p¸ miR-192, miR193-3p, miR-501-3p¸ miR-221, miR-376b-3p) one urinary (miR-30a-5p), and three exosomal (miR-35-5p, miR-301a-3p, miR-1293) were associated with resistance to systemic treatments or treatment failure in mRCC patients. Results showed a fair accuracy of these biomarkers in predicting treatment resistance and overall survival. However, to date, the biomarkers tested have not been validated and their clinical uses are not recommended. Nevertheless, the literature results are encouraging; future large clinical trials are warranted to validate the effectiveness of these tools in clinical decision-making.
