Streptococcus anginosus (S. anginosus) has been identified as a non-Helicobacter pylori (H. pylori) pathogen that promotes gastric tumorigenesis. The study found that S. anginosus is enriched in the gastric mucosa of patients with gastric cancer (GC) and induces acute gastritis in mice. Long-term infection with S. anginosus leads to chronic gastritis, parietal cell atrophy, mucinous metaplasia, and dysplasia in conventional and germ-free mice. S. anginosus accelerates GC progression in carcinogen-induced models and YTN16 GC cell allografts. Mechanistically, the S. anginosus surface protein TMPC interacts with Annexin A2 (ANXA2) on gastric epithelial cells, mediating colonization and activating mitogen-activated protein kinase (MAPK) signaling. ANXA2 knockout abrogates the induction of MAPK by S. anginosus. This study reveals S. anginosus as a non-H. pylori pathogen that promotes gastric tumorigenesis through direct interactions with gastric epithelial cells via the TMPC-ANXA2-MAPK axis.Streptococcus anginosus (S. anginosus) has been identified as a non-Helicobacter pylori (H. pylori) pathogen that promotes gastric tumorigenesis. The study found that S. anginosus is enriched in the gastric mucosa of patients with gastric cancer (GC) and induces acute gastritis in mice. Long-term infection with S. anginosus leads to chronic gastritis, parietal cell atrophy, mucinous metaplasia, and dysplasia in conventional and germ-free mice. S. anginosus accelerates GC progression in carcinogen-induced models and YTN16 GC cell allografts. Mechanistically, the S. anginosus surface protein TMPC interacts with Annexin A2 (ANXA2) on gastric epithelial cells, mediating colonization and activating mitogen-activated protein kinase (MAPK) signaling. ANXA2 knockout abrogates the induction of MAPK by S. anginosus. This study reveals S. anginosus as a non-H. pylori pathogen that promotes gastric tumorigenesis through direct interactions with gastric epithelial cells via the TMPC-ANXA2-MAPK axis.