Streptococcus anginosus induces macrophage pyroptosis and drives gastric "inflammation-to-cancer" transition by activating the NLRP3/IL-1β signaling pathway

Abstract Background Streptococcus anginosus (SA) is enriched in the gastric cancer (GC) microenvironment and correlates with GC risk, but its mechanism in the "inflammation-to-cancer" transition is unclear. This study investigates whether SA induces macrophage pyroptosis through the NLRP3/IL-1β signaling pathway, promoting this transition. Methods Tissue samples from patients (non-H. pylori infected) with chronic superficial gastritis (CSG), intestinal metaplasia (IM), and GC were analyzed for SA infection, pyroptosis-related proteins, and macrophage markers. In vitro, the effects of SA supernatant on GC cell proliferation, migration, and macrophage pyroptosis were examined, with NLRP3 inhibitor MCC950 used for intervention. Metabolomics identified 15(S)-HPETE as a key metabolite. Results Results showed that SA infection load, NLRP3 activation, and macrophage pyroptosis were significantly higher in IM and GC groups than in CSG, with a positive correlation. SA supernatant promoted GC cell proliferation, migration, and macrophage pyroptosis, further driving epithelial-mesenchymal transition (EMT) in GC cells and intestinal metaplasia in gastric cells. These effects were reversed by MCC950. 15(S)-HPETE was found to promote malignant phenotypes in GC cells. Conclusions The study suggests SA induces macrophage pyroptosis via NLRP3/IL-1β signaling, contributing to a pro-inflammatory microenvironment that drives gastric "inflammation-to-cancer" transition, with 15(S)-HPETE as a key mediator.