Abstract B037: Gut microbial metabolism shapes renal cell carcinoma growth

Abstract Background: Clear cell renal cell carcinoma (ccRCC) remains an aggressive cancer, and many patients fail to achieve durable benefit from immune checkpoint inhibitor (ICI) or tyrosine kinase inhibitor (TKI) therapies. Clinical observations suggest that gut microbial metabolism may influence RCC biology, yet the specific metabolites and tumor-intrinsic mechanisms involved are poorly defined. We sought to identify clinically meaningful microbial metabolites elevated in RCC patients and determine their functional impact on tumor growth. Results: Targeted LC-MS/MS metabolomics of RCC patient plasma revealed significantly elevated levels of the gut microbial metabolites, including trimethylamine N-oxide (TMAO) and 5-Hydroxyl Indole Acetic Acid (5-HIAA), compared to healthy controls. Systemic TMAO administration, in mice bearing orthotopic human kidney tumors, increased renal tumor burden in both conventionally housed and germ-free NSG mice. To isolate tumor-intrinsic effects, downstream metabolic and transcriptomic analyses were performed in germ-free mice that were dosed with TMAO (versus vehicle control). Despite the increase in tumor burden, Ki67 and cleaved caspase-3 staining showed no differences, supporting a proliferation-independent growth advantage. Instead, steady state metabolomics analysis demonstrated enrichment of amino acid and redox-associated pathways, while RNA sequencing revealed induction of transcriptional programs linked to cellular plasticity and epithelial–mesenchymal transition. Conclusion: Our findings highlight the importance of TMAO as a tumor-intrinsic oncogenic metabolite in RCC. Our data reveals metabolic and transcriptional adaptations consistent with non-proliferative mechanisms of tumor growth, generating mechanistic hypotheses for how microbial metabolites shape RCC progression. Ongoing studies aim to define the metabolic and epigenetic pathways underlying TMAO-driven tumor fitness and address whether blocking TMAO production (e.g., using TMA lyase inhibitors) might offer a novel strategy to pharmacologically block kidney tumor growth. Citation Format: Vaani A. Nanavaty, Jonathan Mark Brown, Moshe Ornstein, Abhishek A. Chakraborty. Gut microbial metabolism shapes renal cell carcinoma growth [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Innovations in Kidney Cancer Research: From Molecular Insights to Therapeutic Breakthroughs; 2026 Mar 13-16; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2026;86(5_Suppl_2):Abstract nr B037.