Streptococcus anginosus (S. anginosus) is a gram-positive, non-spore-forming, nonmotile bacterium primarily found in the oral cavity, nasopharynx, gastrointestinal tract, and vaginal tract. It is enriched in the gastric mucosa of patients with gastric cancer (GC). This study demonstrates that S. anginosus promotes gastric tumorigenesis by inducing acute gastritis, chronic gastritis, parietal cell atrophy, mucinous metaplasia, and dysplasia in mice. S. anginosus accelerates GC progression in carcinogen-induced gastric tumorigenesis and YTN16 GC cell allografts. Mechanistically, S. anginosus surface protein TMPC interacts with Annexin A2 (ANXA2) on gastric epithelial cells, mediating attachment, colonization, and activation of the mitogen-activated protein kinase (MAPK) signaling pathway. ANXA2 knockout abrogates the induction of MAPK by S. anginosus. This study reveals S. anginosus as a pathogen that promotes gastric tumorigenesis via direct interactions with gastric epithelial cells in the TMPC-ANXA2-MAPK axis. S. anginosus infection disrupts gastric barrier function, promotes cell proliferation, and inhibits apoptosis. The findings suggest that S. anginosus is a non-H. pylori pathogen that contributes to gastric tumorigenesis. The study also shows that S. anginosus induces mucinous metaplasia in germ-free mice and promotes the growth of YTN16 allografts in vivo. S. anginosus activates MAPK signaling through TMPC-ANXA2 interaction, which contributes to its pro-tumorigenic effect. The study highlights S. anginosus as a non-H. pylori pathogenic bacterium driving gastritis and precancerous atrophy-metaplasia-dysplasia sequence, along with reprogrammed gastric microbiome in the murine stomach.Streptococcus anginosus (S. anginosus) is a gram-positive, non-spore-forming, nonmotile bacterium primarily found in the oral cavity, nasopharynx, gastrointestinal tract, and vaginal tract. It is enriched in the gastric mucosa of patients with gastric cancer (GC). This study demonstrates that S. anginosus promotes gastric tumorigenesis by inducing acute gastritis, chronic gastritis, parietal cell atrophy, mucinous metaplasia, and dysplasia in mice. S. anginosus accelerates GC progression in carcinogen-induced gastric tumorigenesis and YTN16 GC cell allografts. Mechanistically, S. anginosus surface protein TMPC interacts with Annexin A2 (ANXA2) on gastric epithelial cells, mediating attachment, colonization, and activation of the mitogen-activated protein kinase (MAPK) signaling pathway. ANXA2 knockout abrogates the induction of MAPK by S. anginosus. This study reveals S. anginosus as a pathogen that promotes gastric tumorigenesis via direct interactions with gastric epithelial cells in the TMPC-ANXA2-MAPK axis. S. anginosus infection disrupts gastric barrier function, promotes cell proliferation, and inhibits apoptosis. The findings suggest that S. anginosus is a non-H. pylori pathogen that contributes to gastric tumorigenesis. The study also shows that S. anginosus induces mucinous metaplasia in germ-free mice and promotes the growth of YTN16 allografts in vivo. S. anginosus activates MAPK signaling through TMPC-ANXA2 interaction, which contributes to its pro-tumorigenic effect. The study highlights S. anginosus as a non-H. pylori pathogenic bacterium driving gastritis and precancerous atrophy-metaplasia-dysplasia sequence, along with reprogrammed gastric microbiome in the murine stomach.