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The tumor microbiota critically shapes responses to immunotherapy; however, the mechanisms by which specific microbial species drive immune checkpoint blockade (ICB) resistance in gastric cancer (GC) remain poorly defined.

Streptococcus anginosus enrichment was assessed in ICB-unresponsive GC tissues from patients and multiple preclinical models. Orthotopic, subcutaneous, and germ-free mono-colonized mouse models were employed to evaluate the impact of S. anginosus on antitumor immunity and programmed cell death protein 1 (PD-1) blockade efficacy. Integrated multi-omics analyses were performed to identify microbiota-derived metabolites, and mechanistic studies investigated their effects on CD8⁺ T-cell function. Therapeutic targeting of integrin α2 (ITGA2) was tested to assess restoration of cytotoxic T-cell activity and sensitization to PD-1 blockade.

S. anginosus was markedly enriched in ICB-non-responsive GC tissues. Colonization with S. anginosus impaired antitumor immunity and promoted PD-1 blockade resistance by suppressing CD8⁺ T-cell effector function. Multi-omics analyses identified kynurenic acid (KA) as a microbiota-derived metabolite selectively enriched following S. anginosus colonization. KA induced ITGA2 expression and inhibited an mTOR-dependent signaling cascade, sustaining cathepsin V expression and attenuating interferon-γ and granzyme B production in CD8⁺ T cells. Therapeutic inhibition of ITGA2 restored CD8⁺ T-cell cytotoxicity and sensitized tumors to PD-1 blockade.

A microbiota-metabolite-immune signaling axis involving S. anginosus, KA, and ITGA2 drives immunotherapy resistance in GC. Therapeutic inhibition of ITGA2 represents a potential strategy to overcome ICB resistance in GC.