Background: RCC is a heterogeneous disease with variable responses to systemic therapy. Tumor microenvironment (TME) and mi-RNA expression has been associated with prognosis in RCC, but its predictive role based on treatment remains uncertain. CABOPRE (EudraCT 2018-001201-93) was a multicentre, single-arm, phase II trial investigating perioperative cabozantinib (cabo) in mRCC patients with intermediate/poor IMDC prognosis. Primary objective was to assess overall response rate (ORR). Between December 2018 and December 2020, 15 patients were included and evaluable for ORR. Partial response was achieved in 4 patients (26%), stable disease in 10 patients (66%), and 1 progressed (6%). Cytoreductive nephrectomy was performed in 11 patients (73%). Updated overall survival at 2 years was 60%. In this work, we analysed the change expression differences of selective mi-RNAs in plasma and TME previous before and after 12 first weeks of perioperatory cabo. Methods: Plasma samples were used for RNA purification using Plasma miRNEasy System from Thermofisher Scientific. Nanostring platform, Human v3 miRNA Assay cartridge from nanostring and by bioinformatics’ analyses using Nsolver software for miRNA discovery and using TaqMan Advance miRNA System (Applied Biosystems) for validation. TME (tumor and stroma cell) was analysed with Tissue microarray using Digital Spatial Profiler (DSP) on a subset of 12 paired samples (treatment-naïve/ 12 weeks post-cabo). We used GeoMx DSP platform (Nanostring) and GeoMx RNA immune pathways Panel .Data obtained was analysed using a GeoMx Analysis Suite 2.3. Results: Differentially Expressed miRNAs: We identified 9 miRNAs with significant differential expression when comparing samples before and after treatment (6 downregulated and 3 upregulated). Efficacy Association: In our discovery cohort, 6 miRNAs were differentially expressed between responder cabo patients. These miRNAs were further validated. miR-150-5p (Up), miR-590-5p (Up), and miR-31-5p (Down) displayed particularly promising performance in responder patients. Microenviromental Dynamics: DSP analysis revealed differential expression profiles related to immune and angiogenesis processes depending on cabo response. Conclusions: After 2 years of follow-up, our data demonstrates the feasibility and safety of perioperative cabo in mRCC. Molecular analysis reveals 3 specific mi-RNAS whose expression patterns correlated with cabo responses, potentially serving as predictive biomarkers. Additionally, DSP analysis underscores the substantial microenvironmental heterogeneity within kidney cancer, highlighting its complex nature. These findings collectively contribute to our understanding of mRCC management, offering promising avenues for personalized treatment approaches.