Pan-cancer circular genomics identifies intratumoral Staphylococcus lugdunensis as a metabolic driver in bladder cancer

SUMMARY Intratumoral microbiota play key roles in cancer but are challenging to profile due to low biomass. We developed CIRCMIP, an enzymatic pipeline that eliminates linear DNA to enrich bacterial genomes, achieving 100-fold higher sensitivity than standard metagenomics. Applied to 312 pan-cancer specimens, CIRCMIP identified Staphylococcus lugdunensis as a signature bacterium enriched in early-stage bladder cancer (BLCA), where its presence predicts poor survival. Integrated modeling and lipidomics revealed that Staphylococcus lugdunensis colonization drives aberrant lipid metabolism with secretion of LPC14:0. Both Staphylococcus lugdunensis and LPC14:0 drive BLCA progression by promoting fatty acid uptake and β-oxidation. Mechanistically, chemical proteomics revealed LPC14:0 as a direct PPARδ ligand, binding via hydrogen bonds with Thr292/Thr289. This activation upregulates fatty acid transporters (CD36, FABP4) and metabolic enzymes (ACOX2), fueling malignant proliferation. Furthermore, CIRCMIP-derived biomarkers show robust diagnostic accuracy, establishing a new research paradigm and revealing the Staphylococcus lugdunensis-LPC14:0-PPARδ axis as a therapeutic target in bladder cancer. HIGHLIGHT CIRCMIP leverages DNA circularity to achieve 100-fold sensitivity in pan-cancer bacteriome profiling. Staphylococcus lugdunensis is a bacterial signature in early-stage bladder cancer that predicts poor patient survival. Bacteria-derived LPC14:0 acts as a direct ligand for PPARδ to drive host malignant metabolic reprogramming. Targeting the Staphylococcus lugdunensis-LPC14:0-PPARδ axis abrogates malignant progression in bladder cancer. Competing Interest Statement The authors have declared no competing interest. Footnotes ↵14 Lead contact