Streptococcus anginosus -associated kynurenic acid drives PD-1 blockade resistance through an ITGA2-mTOR-CTSV axis in gastric cancer
Yingxin Ren, Xiang Yu, Jiaqiang Jiang, Jinlong Luo, Cuiyin Zhao, Xinyuan Mao, Yijie Xi, Junting He, Chao Yu, Yanfeng HuBackground
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.
Methods
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.
Results
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.
Conclusions
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.