Bacteria inside kidney tumors associate with myeloid inflammation and disease progression: A TRACERx Renal study.
BACKGROUND Intratumoral bacteria are increasingly recognized as active contributors to neutrophil-driven inflammation and disease progression in solid tumors. Yet, in clear cell renal cell carcinoma (ccRCC), where myeloid inflammation is a key feature of aggressive disease, live bacterial presence, their intratumoral distribution, and interaction with the tumor microenvironment remain unexplored. METHODS We genetically characterized the microbiome of primary ccRCC tumors across two independent cohorts (TRACERx: 616 samples, 143 patients; The Cancer Genome Atlas [TCGA]: 511 samples and patients), confirming live bacterial presence through culture. Multi-regional sampling enabled within-tumor analysis of bacterial distribution. Associations with the tumor microenvironment were explored at scale using bulk RNA sequencing (RNA-seq) across both cohorts and corroborated in depth through spatial transcriptomics and in vitro infection assays. FINDINGS Across both cohorts, the commensal Cutibacterium emerged as the dominant genus, accumulating in discrete niches enriched toward the tumor center and associating with more advanced (TRACERx p = 0.024; TCGA p = 0.0011) tumors and shorter progression-free survival (TRACERx p = 0.0022; TCGA p = 4.4 × 10-4). Both across and within tumors, Cutibacterium accumulation associated with neutrophil recruitment and myeloid inflammation. In vitro, Cutibacterium induced sustained expression of neutrophil-attracting chemokines in macrophages, recapitulating patient tumor findings. CONCLUSIONS These findings establish intratumoral bacteria as novel prognostic components of the ccRCC tumor microenvironment and suggest an active role in shaping local myeloid inflammation, laying the groundwork for investigating their potential as therapeutic targets. FUNDING This work was supported by the Francis Crick Institute (Cancer Research UK, MRC, Wellcome Trust). TRACERx Renal is funded by Cancer Research UK (C50947/A18176).