Intratumoral Fusobacterium nucleatum Recruits Tumor-Associated Neutrophils to Promote Gastric Cancer Progression and Immune Evasion.

Abstract

Intratumoral microbiota can impact the development and progression of many types of cancer, including gastric cancer (GC). A better understanding of the precise mechanisms by which microbiota support GC could lead to improved therapeutic approaches. Here, we investigated the effect of intratumoral microbiota on the tumor immune microenvironment (TIME) during GC malignant progression. Analysis of human GC tissues with 16S rRNA amplicon sequencing revealed that Fusobacterium nucleatum (F. nucleatum) was significantly enriched in GC tissues with lymph node metastasis and correlated with a poor prognosis. F. nucleatum infection spontaneously induced chronic gastritis and promoted gastric mucosa dysplasia in mice. Furthermore, GC cells infected with F. nucleatum showed accelerated growth in immunocompetent mice compared to immunodeficient mice. Single-cell RNA sequencing uncovered that F. nucleatum recruited tumor-associated neutrophils (TANs) to reshape the tumor immune microenvironment. Mechanistically, F. nucleatum invaded GC cells and activated IL-17/NF-κB/RelB signaling, inducing TAN recruitment. F. nucleatum also stimulated TAN differentiation into the pro-tumoral subtype and subsequent promotion of PD-L1 expression, further facilitating GC immune evasion while also enhancing the efficacy of anti-PD-L1 antibody therapy. Together, this data uncovers mechanisms by which F. nucleatum affects GC immune evasion and immunotherapy efficacy, providing insights for developing effective treatment strategies.