Akkermansia muciniphila enhances the antitumour efficacy of αPD-1 therapy in gastric cancer by remodelling the tumour immune microenvironment

Abstract

There is growing advocacy for employing probiotics as adjuncts to potentiate immune checkpoint blockade (ICB) in cancer therapy. In this study, we investigated whether the probiotic Akkermansia muciniphila (A. muciniphila) could enhance the antitumour responses to anti-PD-1 (αPD-1) in gastric cancer (GC) by reshaping the tumour microenvironment (TME). A subcutaneous GC model was established in male strain 615 mice by inoculating 1 × 10⁶ Mouse Forestomach Carcinoma (MFC) cells on Day 10. A. muciniphila was given by daily oral gavage (1 × 10⁹ CFU per mouse) from Day 0 to Day 31, and the αPD-1 antibody was administered intraperitoneally (100 μg per mouse) every 3 days from Day 16 to Day 31. Tumour volume was recorded every 3 days, and tumours were collected on Day 31 for histology, flow cytometry, enzyme-linked immunosorbent assay (ELISA), 16S rRNA sequencing and statistical analyses. Combined treatment with A. muciniphila and αPD-1 significantly inhibited subcutaneous tumour growth (P < 0.0001) and promoted tumour cell apoptosis (P < 0.0001). A. muciniphila increased the therapeutic effectiveness of αPD-1 treatment by driving CD8⁺ T-cell accumulation within the TME (P < 0.0001). Supplementation with A. muciniphila reshaped the leading constituents of the gut microbiota and was associated with a significant fall in the relative abundance of Escherichia coli (E. coli) (P = 0.0170). By driving CD8⁺ T-cell infiltration and activation and reshaping the intestinal microbiota, A. muciniphila augmented the efficacy of αPD-1 therapy against gastric tumours.