Fusobacterium nucleatum-driven CX3CR1+ PD-L1+ phagocytes route to tumor tissues and reshape tumor microenvironment
The intracellular bacterium Fusobacterium nucleatum (Fn) mediates tumorigenesis and progression in colorectal cancer (CRC). However, the origin of intratumoral Fn and the role of Fn-infected immunocytes in the tumor microenvironment remain unclear. Here, we observed that Fn-infected neutrophils/macr...
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Taylor & Francis Group
2025-12-01
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| Series: | Gut Microbes |
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| Online Access: | https://www.tandfonline.com/doi/10.1080/19490976.2024.2442037 |
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| author | Fangfang Chen Songhe Guo Yiqiu Li Yongfan Lu Le Liu Shengxin Chen Jun An Ge Zhang |
| author_facet | Fangfang Chen Songhe Guo Yiqiu Li Yongfan Lu Le Liu Shengxin Chen Jun An Ge Zhang |
| author_sort | Fangfang Chen |
| collection | DOAJ |
| description | The intracellular bacterium Fusobacterium nucleatum (Fn) mediates tumorigenesis and progression in colorectal cancer (CRC). However, the origin of intratumoral Fn and the role of Fn-infected immunocytes in the tumor microenvironment remain unclear. Here, we observed that Fn-infected neutrophils/macrophages (PMNs/MΦs), especially PMNs, accumulate in tumor tissues and fecal Fn abundance correlates positively with an abundance of blood PD-L1+ PMNs in CRC patients. Moreover, Fn accumulates in tumor tissues of tumor-bearing mice via intragingival infection and intravenous injection. Mechanistically, Fn can survive inside PMNs by reducing intracellular ROS levels and producing H2S. Specifically, the lysozyme inhibitor Fn1792 as a novel virulence factor of Fn suppressed apoptosis of phagocytes by inducing CX3CR1 expression. Furthermore, Fn-driven CX3CR1+PD-L1+ phagocytes transfer intracellular Fn to tumor cells, which recruit PMNs/MΦs through the CXCL2/8-CXCR2 and CCL5/CCR5 axes. Consequently, CX3CR1+PD-L1+ PMNs infiltration promotes CRC metastasis and weakens the efficacy of immunotherapy. Treatment with the doxycycline eradicated intracellular Fn, thereby reducing the CX3CR1+PD-L1+ PMNs populations and slowing Fn-promoted tumor growth and metastasis in mice. These results suggest phagocytes as Fn-presenting cells use mutualistic strategies to home to tumor tissues and induce immunosuppression, and treatment with ROS-enhanced antibiotics can inhibit Fn-positive tumor progression. |
| format | Article |
| id | doaj-art-23d574e5bcbd43dca4f2f4698f00a697 |
| institution | OA Journals |
| issn | 1949-0976 1949-0984 |
| language | English |
| publishDate | 2025-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Gut Microbes |
| spelling | doaj-art-23d574e5bcbd43dca4f2f4698f00a6972025-08-20T01:57:09ZengTaylor & Francis GroupGut Microbes1949-09761949-09842025-12-0117110.1080/19490976.2024.2442037Fusobacterium nucleatum-driven CX3CR1+ PD-L1+ phagocytes route to tumor tissues and reshape tumor microenvironmentFangfang Chen0Songhe Guo1Yiqiu Li2Yongfan Lu3Le Liu4Shengxin Chen5Jun An6Ge Zhang7Department of Microbial and Biochemical Pharmacy, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, ChinaState Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, ChinaDepartment of Microbial and Biochemical Pharmacy, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, ChinaDepartment of Microbial and Biochemical Pharmacy, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, ChinaDepartment of Gastroenterology, Integrated Clinical Microecology Center, Shenzhen Hospital, Southern Medical University, Shenzhen, ChinaGraduate School, Chinese PLA General Hospital, Beijing, ChinaDepartment of Cardiothoracic Surgery, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, ChinaDepartment of Microbial and Biochemical Pharmacy, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, ChinaThe intracellular bacterium Fusobacterium nucleatum (Fn) mediates tumorigenesis and progression in colorectal cancer (CRC). However, the origin of intratumoral Fn and the role of Fn-infected immunocytes in the tumor microenvironment remain unclear. Here, we observed that Fn-infected neutrophils/macrophages (PMNs/MΦs), especially PMNs, accumulate in tumor tissues and fecal Fn abundance correlates positively with an abundance of blood PD-L1+ PMNs in CRC patients. Moreover, Fn accumulates in tumor tissues of tumor-bearing mice via intragingival infection and intravenous injection. Mechanistically, Fn can survive inside PMNs by reducing intracellular ROS levels and producing H2S. Specifically, the lysozyme inhibitor Fn1792 as a novel virulence factor of Fn suppressed apoptosis of phagocytes by inducing CX3CR1 expression. Furthermore, Fn-driven CX3CR1+PD-L1+ phagocytes transfer intracellular Fn to tumor cells, which recruit PMNs/MΦs through the CXCL2/8-CXCR2 and CCL5/CCR5 axes. Consequently, CX3CR1+PD-L1+ PMNs infiltration promotes CRC metastasis and weakens the efficacy of immunotherapy. Treatment with the doxycycline eradicated intracellular Fn, thereby reducing the CX3CR1+PD-L1+ PMNs populations and slowing Fn-promoted tumor growth and metastasis in mice. These results suggest phagocytes as Fn-presenting cells use mutualistic strategies to home to tumor tissues and induce immunosuppression, and treatment with ROS-enhanced antibiotics can inhibit Fn-positive tumor progression.https://www.tandfonline.com/doi/10.1080/19490976.2024.2442037Fusobacterium nucleatumphagocytesFn1792CX3CR1+PD-L1+tumor microenvironment |
| spellingShingle | Fangfang Chen Songhe Guo Yiqiu Li Yongfan Lu Le Liu Shengxin Chen Jun An Ge Zhang Fusobacterium nucleatum-driven CX3CR1+ PD-L1+ phagocytes route to tumor tissues and reshape tumor microenvironment Gut Microbes Fusobacterium nucleatum phagocytes Fn1792 CX3CR1+PD-L1+ tumor microenvironment |
| title | Fusobacterium nucleatum-driven CX3CR1+ PD-L1+ phagocytes route to tumor tissues and reshape tumor microenvironment |
| title_full | Fusobacterium nucleatum-driven CX3CR1+ PD-L1+ phagocytes route to tumor tissues and reshape tumor microenvironment |
| title_fullStr | Fusobacterium nucleatum-driven CX3CR1+ PD-L1+ phagocytes route to tumor tissues and reshape tumor microenvironment |
| title_full_unstemmed | Fusobacterium nucleatum-driven CX3CR1+ PD-L1+ phagocytes route to tumor tissues and reshape tumor microenvironment |
| title_short | Fusobacterium nucleatum-driven CX3CR1+ PD-L1+ phagocytes route to tumor tissues and reshape tumor microenvironment |
| title_sort | fusobacterium nucleatum driven cx3cr1 pd l1 phagocytes route to tumor tissues and reshape tumor microenvironment |
| topic | Fusobacterium nucleatum phagocytes Fn1792 CX3CR1+PD-L1+ tumor microenvironment |
| url | https://www.tandfonline.com/doi/10.1080/19490976.2024.2442037 |
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