<p>Papillary thyroid carcinoma (PTC) is the most common type of thyroid cancer. The “mild” clinical behavior of PTC often leads to underestimation of the complexity of its treatment. Ruminococcus (Rum) is a cancer-related intestinal flora. Further study on its functional mechanism is expected to provide a new direction for microbial targeted therapy of cancer. Therefore, the aim of this study was to investigate the therapeutic effect of Rum on PTC and its related mechanism. Rum upregulated the mRNA expression level of RBM15 in BCPAP and KTC-1 cells, decreased their cell viability, promoted pyroptotic signaling, and inhibited their invasion and migration, as well as reduced the volume and weight of tumor tissue and aggravated their pathological injuries. Moreover, Rum downregulated MMP2 and MMP9 mRNA and protein expression levels and upregulated IFN-γ, IL-1β, and IL-18 expression levels, as well as NLRP3, ASC, Caspase-1 mRNA and protein expression levels, the m6A methylation content, and the m6A methylation of NLRP3 in vivo and in vitro. In addition, knocking down RBM15 effectively reversed the effects of Rum mentioned above in vivo and in vitro. Mechanistically, Rum activates the NLRP3/ASC/Caspase-1 axis–mediated pyroptotic signaling in PTC by upregulating RBM15 to increase the N6-methyladenosine methylation modulation of NLRP3, thereby providing a novel strategy and target for the clinical treatment of PTC.</p>