Gut microbe promotes papillary thyroid carcinoma progression by upregulating the oncogene and fostering an immunosuppressive tumor microenvironment.

Growing evidence suggests a link between the gut microbiome and papillary thyroid carcinoma (PTC), but the causal relationships and the impact on the tumor immune microenvironment (TME) are poorly understood. This study aimed to elucidate the causal role of specific gut microbes in PTC and uncover the underlying immunological and molecular mechanisms. We employed a multi-stage design, beginning with a two-sample Mendelian randomization (MR) analysis using large-scale GWAS data to infer causality. Findings were then validated in 450 PTC patients from The Cancer Genome Atlas (TCGA) by analyzing correlations between microbial abundance, gene expression, immune cell infiltration, and survival. Finally, the core mechanism was confirmed through extensive experiments with PTC cell lines. Our MR analysis identified a causal association between a genetically predicted higher abundance of the genus and an increased risk of PTC (Odds Ratio [OR] = 2.06, 95% Confidence Interval [CI]: 1.34-3.16). In the TCGA cohort, higher intratumoral signals of was significantly correlated with an immunosuppressive TME, characterized by increased infiltration of M2 macrophages (ρ = 0.25, p < 0.001) and decreased CD8+ T cells (ρ = -0.19, p = 0.008). Mechanistically, abundance was also strongly associated with the upregulation of the oncogene (ρ = 0.35, p < 0.001), which independently predicted poorer overall survival (Hazard Ratio [HR] = 2.15, p = 0.004). experiments confirmed that supernatant from culture not only upregulated expression and promoted PTC cell proliferation but also enhanced invasion and induced cell de-differentiation. Importantly, pharmacological inhibition of TRK signaling reversed the bacteria-induced aggressive phenotype. Our integrated analysis provides robust, multi-layered evidence for a causal role of in promoting PTC progression. We define a novel gut-thyroid axis where contributes to PTC development by upregulating the oncogene and shaping a pro-tumorigenic, immunosuppressive microenvironment. These findings reveal a new dimension of host-microbe interaction in thyroid cancer and highlight the TME as a key downstream target of microbial influence.