Gut microbiome impact on systemic therapy outcomes in metastatic renal cell carcinoma: a systematic review

BACKGROUND AND OBJECTIVE: Metastatic renal cell carcinoma (mRCC) treatment with immune checkpoint inhibitors (ICIs) and vascular endothelial growth factor–tyrosine kinase inhibitors (VEGF-TKIs) yields durable benefit in a subset of patients, yet primary resistance remains frequent. Emerging data implicate the gut microbiome as a determining factor of systemic therapy efficacy. This review systematically evaluates clinical evidence on antibiotics (ATBs), probiotics, dietary interventions, and fecal microbiota transplantation (FMT) in modulating the gut microbiome to influence outcomes in adult patients with mRCC. METHODS: Eligible studies included adult (≥ 18 year) RCC cohorts receiving microbiome interventions versus standard care, reporting objective response rate (ORR), progression-free survival (PFS), overall survival (OS), or immune-related adverse events (irAEs). KEY FINDINGS AND LIMITATIONS: Six studies (N = 4738) met criteria: three retrospective cohorts linking peri-ICI ATB exposure to inferior ORR (12.9–34.8%), shorter PFS (hazard ratios [HR] 1.96–3.10), and OS (HR 3.5); one prospective RCT (n = 20) demonstrating engraftment of Bifidobacterium animalis yogurt during VEGF-TKI therapy with enrichment of Akkermansia muciniphila and trends to longer PFS; and one phase II RCT abstract (n = 50) showing FMT from an ICI responder improved 1-year PFS (66.7% vs. 35.0%, p = 0.036) and ORR (54% vs. 28%) in pembrolizumab + axitinib recipients. CONCLUSIONS AND CLINICAL IMPLICATIONS: ATB-induced dysbiosis compromises ICI efficacy in mRCC; probiotics and FMT exhibit promise to augment immunotherapy and targeted therapy. Prospective, biomarker-driven RCTs with standardized microbiome assays are needed before routine clinical implementation.