Streptococcus anginosus-generated succinate promotes the progression of gastric cancer via the succinate/SUCNR1/ABRAXAS1 axis.

Streptococcus anginosus (S. anginosus) has recently been implicated in promoting gastric carcinogenesis, but the underlying mechanism of S. anginosus and its metabolites in gastric carcinogenesis is still unclear. We found that S. anginosus is enriched in gastric cancer (GC) and that a high abundance of S. anginosus is associated with a poor prognosis of GC. Both S. anginosus and S. anginosus conditioned medium (S. a CM) promoted the proliferation, invasion, and migration of GC cells, inhibited cell apoptosis in vitro, and aggravated gastric inflammation and mucus metaplasia in vivo. Succinate is identified as the functional metabolite promoting gastric carcinogenesis in S. a CM. Knockdown of succinate receptor 1 (SUCNR1) or treatment with SUCNR1 inhibitors inhibited the tumor-promoting effect of succinate. Mechanistically, S. anginosus-derived succinate binds to SUCNR1 in gastric epithelial cells, and SUCNR1 directly interacts with ABRAXAS1 to activate the phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway and promotes the progression of GC.