Xuedong Li

S. pneumoniae promotes metabolic reprogramming and enhances pazopanib tolerance in ccRCC cells.

S. pneumoniae–mediated pazopanib resistance in ccRCC xenografts requires psaA.

Summary of clinical ccRCC patients

The details of primary antibodies used for western blot, ChIP, immunoprecipitation, immunohistochemistry and immunofluorescence

The primers sequences used for ChIP-qPCR

Table S1 from 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.

Fatty acid metabolism-related pathways in GSEA analysis

Distinct bacterial community diversity between PAZ-S and PAZ-R samples.