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<p>The facultative intracellular bacterium <i>Fusobacterium nucleatum</i> (Fn) promotes tumorigenesis and progression in esophageal squamous cell carcinoma (ESCC). The intracellular survival strategy of Fn and whether Fn can spread through cell‒cell contact in intratumoral tissues and, if so, the underlying mechanisms and implications are currently unknown. Here, we report that Fn accumulates in macrophages from ESCC tumors and paracancerous normal tissues. We further revealed that Fn-induced macrophage mitophagy through the PINK1-Parkin-independent pathway decreases excessive mitochondrial ROS production to promote survival. Furthermore, Fn drives a biphasic metabolic switch between glycolysis and oxidative phosphorylation in macrophages to support the bioenergetic demands of survival. Notably, Fn can be carried by macrophages to tumor sites, where it promotes tumor metastasis via the CCL2-CCR2 axis in ESCC. Treatment with a mitochondrial division inhibitor (mdivi-1) reduced the intracellular Fn concentration and inhibited Fn-positive tumor metastasis in mice. This study highlights the crucial interactions between Fn and host macrophages that influence tumor progression. These findings indicate that mitophagy inhibitors or mitophagy machinery targeting may serve as efficient therapeutic strategies to treat Fn-positive tumors.</p><p></p>

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Fusobacterium nucleatum-induced mitophagy in macrophages supports intracellular bacterial persistence and promotes esophageal squamous cell carcinoma metastasis

  • 期刊论文

  • 发表日期：

    2026年5月22日

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  • Fangfang Chen,
  • Yulin Liu,
  • Han Xiao,
  • Xiaoyun Pan,
  • Shuyi Luo,
  • Yiqiu Li,
  • Shengxin Chen,
  • Songhe Guo,
  • Ge Zhang

摘要

The facultative intracellular bacterium Fusobacterium nucleatum (Fn) promotes tumorigenesis and progression in esophageal squamous cell carcinoma (ESCC). The intracellular survival strategy of Fn and whether Fn can spread through cell‒cell contact in intratumoral tissues and, if so, the underlying mechanisms and implications are currently unknown. Here, we report that Fn accumulates in macrophages from ESCC tumors and paracancerous normal tissues. We further revealed that Fn-induced macrophage mitophagy through the PINK1-Parkin-independent pathway decreases excessive mitochondrial ROS production to promote survival. Furthermore, Fn drives a biphasic metabolic switch between glycolysis and oxidative phosphorylation in macrophages to support the bioenergetic demands of survival. Notably, Fn can be carried by macrophages to tumor sites, where it promotes tumor metastasis via the CCL2-CCR2 axis in ESCC. Treatment with a mitochondrial division inhibitor (mdivi-1) reduced the intracellular Fn concentration and inhibited Fn-positive tumor metastasis in mice. This study highlights the crucial interactions between Fn and host macrophages that influence tumor progression. These findings indicate that mitophagy inhibitors or mitophagy machinery targeting may serve as efficient therapeutic strategies to treat Fn-positive tumors.