biostudies-literatureZhang TThe Fundamental Research Funds for the Central Universities, Sun Yat-sen UniversityGuangdong Provincial Applied Science and Technology Research and Development Program (Guangdong Foundation for Program of Science and Technology Research)Guangzhou Science and Technology Innovation Center (Guangdong Provincial Modern Agricultural Science and Technology Innovation Center)Guangdong Provincial Key Laboratory of Construction FoundationGuangdong Provincial Applied Science and Technology Research and Development ProgramNational Natural Science Foundation of ChinaGDAS’ Project of Science and Technology DevelopmentNational Natural Science Foundation of China (NSFC)Fundamental Research Funds for the Central Universities (Fundamental Research Fund for the Central Universities)Guangdong Provincial Natural Science Foundation project grantGuangzhou Nansha Technology Plan ProjectGuangzhou Science, Technology and Innovation Commission (Bureau of Science and Information Technology of Guangzhou Municipality)Fundamental Research Funds for the Central UniversitiesNational Natural Science Foundation of China grantGuangzhou Science, Technology and Innovation CommissionGuangdong Provincial Key Laboratory of Construction Foundation ()Key-Area Research and Development Program of Guangdong Province grantGuangdong Academy of Sciences (GDAS)Guangdong Academy of SciencesGuangdong Province Excellent Youth Team ProjectGuangzhou Science and Technology Innovation CenterGuangdong Provincial Health Commission grantGDAS' Project of Science and Technology Development1819-1841https://www.ebi.ac.uk/biostudies/studies/S-EPMC12079103biostudies-literatureUnknown85(10)Intratumoral microbiota can affect the development and progression of many types of cancer, including gastric cancer. A better understanding of the precise mechanisms by which microbiota support gastric cancer could lead to improved therapeutic approaches. In this study, we investigated the effect of intratumoral microbiota on the tumor immune microenvironment during gastric cancer malignant progression. Analysis of human gastric cancer tissues with 16S rRNA amplicon sequencing revealed that Fusobacterium nucleatum was significantly enriched in gastric cancer 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, gastric cancer cells infected with F. nucleatum showed accelerated growth in immunocompetent mice compared with immunodeficient mice. Single-cell RNA sequencing uncovered that F. nucleatum recruited tumor-associated neutrophils (TAN) to reshape the tumor immune microenvironment. Mechanistically, F. nucleatum invaded gastric cancer cells and activated IL17/NF-κB/RelB signaling, inducing TAN recruitment. F. nucleatum also stimulated TAN differentiation into the protumoral subtype and subsequent promotion of PD-L1 expression, further facilitating gastric cancer immune evasion while also enhancing the efficacy of anti-PD-L1 antibody therapy. Together, these data uncover mechanisms by which F. nucleatum affects gastric cancer immune evasion and immunotherapy efficacy, providing insights for developing effective treatment strategies. Significance: Intratumoral F. nucleatum activates NF-κB signaling to facilitate gastric cancer immune evasion by promoting tumor-associated neutrophil recruitment that sensitizes tumors to immune checkpoint blockade therapy.Cancer researchIntratumoral Fusobacterium nucleatum Recruits Tumor-Associated Neutrophils to Promote Gastric Cancer Progression and Immune Evasion.PMC1207910324qnpy3292023A15151111522023A1515011187A20240522024A15150107392021A15151107592022A1515011534821732392022GDASZH-2022010101821006262023MS0032022B11110700062024B1515040029824729042024MS006Zhai ELiu JCai SChen JWu QLiang ZZhao ZLiu YYe LLi YZhang TQian YLi ZWei RZhao RHuang ZMa JXu XfalseIntratumoral Fusobacterium nucleatum Recruits Tumor-Associated Neutrophils to Promote Gastric Cancer Progression and Immune Evasion.Intratumoral microbiota can affect the development and progression of many types of cancer, including gastric cancer. A better understanding of the precise mechanisms by which microbiota support gastric cancer could lead to improved therapeutic approaches. In this study, we investigated the effect of intratumoral microbiota on the tumor immune microenvironment during gastric cancer malignant progression. Analysis of human gastric cancer tissues with 16S rRNA amplicon sequencing revealed that Fusobacterium nucleatum was significantly enriched in gastric cancer 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, gastric cancer cells infected with F. nucleatum showed accelerated growth in immunocompetent mice compared with immunodeficient mice. Single-cell RNA sequencing uncovered that F. nucleatum recruited tumor-associated neutrophils (TAN) to reshape the tumor immune microenvironment. Mechanistically, F. nucleatum invaded gastric cancer cells and activated IL17/NF-κB/RelB signaling, inducing TAN recruitment. F. nucleatum also stimulated TAN differentiation into the protumoral subtype and subsequent promotion of PD-L1 expression, further facilitating gastric cancer immune evasion while also enhancing the efficacy of anti-PD-L1 antibody therapy. Together, these data uncover mechanisms by which F. nucleatum affects gastric cancer immune evasion and immunotherapy efficacy, providing insights for developing effective treatment strategies. Significance: Intratumoral F. nucleatum activates NF-κB signaling to facilitate gastric cancer immune evasion by promoting tumor-associated neutrophil recruitment that sensitizes tumors to immune checkpoint blockade therapy.2025-01-01T00:00:00Z2025 May2026-06-02T20:48:55.288Z2026-04-20T03:14:33.772ZS-EPMC120791033999270810.1158/0008-5472.CAN-24-2580