Tumor-Resident Streptococcus pneumoniae Promotes Malignant Progression and Pazopanib Resistance in Clear Cell Renal Cell Carcinoma

Persistent drug resistance to tyrosine kinase inhibitors (TKI) has become a hurdle in extending the survival of patients with clear cell renal cell carcinoma (ccRCC). Through microbiome screening of patient samples from a ccRCC cohort treated with the TKI pazopanib, we identified Streptococcus pneumoniae as the dominant intratumoral microbiota in pazopanib-resistant ccRCC samples. Further investigation revealed that S. pneumoniae reprogrammed lipid metabolism in ccRCC cells by depleting manganese (Mn2+) from the tumor microenvironment, consequently facilitating malignant progression and development of pazopanib resistance. S. pneumoniae suppressed S-nitrosylation of tripartite motif-containing protein 28 (TRIM28) by diminishing Mn2+ levels, allowing TRIM28 to physically interact with the transcription factor SP1 to promote the transcription of solute carrier family 27 member 1 (SLC27A1) and lipid deposition. Taken together, these findings indicate that tumor-resident S. pneumoniae plays an important role in conferring pazopanib resistance, suggesting that S. pneumoniae could serve as a potential biomarker of pazopanib response in ccRCC. SIGNIFICANCE: Streptococcus pneumoniae is an intratumoral bacteria that drives pazopanib resistance in renal cell carcinoma, highlighting the potential of targeting the tumor microbiome as a strategy to improve treatment outcomes in cancer patients.