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

Abstract Persistent drug resistance to tyrosine kinase inhibitors 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 tyrosine kinase inhibitor pazopanib, we identified Streptococcus pneumoniae (S. pneumoniae) as the dominant intratumoral microbiota in pazopanib-resistant ccRCC samples. Further investigation revealed that S. pneumoniae reprogramed 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.