Abstract
BACKGROUND: Papillary thyroid carcinoma (PTC) exhibits epitranscriptomic dysregulation and tumor-resident microbiota alterations, yet potential links between these processes remain unclear. We investigated whether intratumoral bacterial features are associated with METTL3-dependent programs in PTC. METHODS: We profiled intratumoral microbiota from PTC and adjacent thyroid tissues and integrated these data with tumor gene-expression analyses. Candidate genes associated with the abundance of Delftia lacustris were prioritized by a prespecified scheme (FDR rank, effect size/consistency, pathway plausibility, and experimental tractability). Functional assays (gain/loss of function, rescue) tested METTL3 and downstream DMTF1 effects on PTC cell phenotypes (proliferation, colony formation, apoptosis/cell cycle, migration/invasion). Appropriate statistical tests with multiple-comparison correction were applied; exact P values and effect sizes are reported in the figure legends and Source Data. RESULTS: Reduced intratumoral D. lacustris abundance was inversely associated with METTL3 expression and with PTC occurrence. Based on prioritization, METTL3 was selected for mechanistic interrogation. METTL3 overexpression enhanced proliferation and clonogenicity, whereas METTL3 knockdown produced the opposite effects; DMTF1 re-expression rescued METTL3-knockdown phenotypes, delineating a METTL3-DMTF1 proliferative axis in PTC cells. These tumor-intrinsic results, together with the microbiome association, nominate D. lacustris as a tumor microenvironment (TME)–coupled biomarker of a METTL3-high epitranscriptomic state. CONCLUSIONS: We identify a METTL3-DMTF1 axis that promotes PTC cell growth and show that lower intratumoral D. lacustris abundance is associated with higher METTL3 levels and with PTC. Given the cross-sectional design, these relationships should be interpreted as associative (not causal). The data generate testable hypotheses for microbiome–epitranscriptome crosstalk in the PTC TME, motivating spatial, longitudinal, and perturbational studies to resolve directionality. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12935-026-04183-9.