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Background <p>Intratumoral <i>Fusobacterium nucleatum</i> (<i>Fn</i>) infection is closely associated with poor prognosis in esophageal cancer (EC) due to its impact on the tumor microenvironment (TME). The tumor cell-intrinsic cyclic GMP–AMP synthase (cGAS)–stimulator of interferon genes (STING) pathway is critical for regulating immune cell activation in the TME. However, the link between intratumoral <i>Fn</i> infection and the activation of the cGAS–STING pathway in tumor cells, as well as its effects on EC progression, remains largely unknown.</p> Methods <p>In the present study, we investigated the impact of intratumoral <i>Fn</i> infection on the activation of the tumor cell-intrinsic cGAS–STING pathway and EC progression by analyzing our own EC cohort and performing in vitro experiments using co-cultures of EC-cell lines and <i>Fn</i>.</p> Results <p>The expression of tumor cell-intrinsic STING was significantly associated with worse prognosis in <i>Fn</i>-high EC patients. Exposure to <i>Fn</i> significantly activated the STING pathway in EC cells. RNA-seq analysis revealed that exposure to <i>Fn</i> markedly activated cytokine–chemokine-related signaling pathways and induced the expression of several cytokines and chemokines in STING-expressing EC cells. Among the differentially expressed cytokine and chemokine genes in EC cells co-cultured with <i>Fn</i>, analysis of TCGA datasets demonstrated that the expression of <i>CCL20</i>, <i>CXCL10</i>, and <i>CSF2</i> may be associated with poor prognosis in EC patients.</p> Conclusion <p>We revealed that the activation of the STING signaling pathway and the subsequent expression of cytokines and chemokines in EC cells induced by <i>Fn</i> infection may be closely associated with poor prognosis in EC patients.</p>

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Activation of the tumor cell-intrinsic STING pathway induced by Fusobacterium nucleatum is associated with poor prognosis in esophageal cancer patients

  • 期刊论文

  • 发表日期：

    2025年2月14日

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  • Shotaro Nakajima,
  • Katsuharu Saito,
  • Satoshi Fukai,
  • Mei Sakuma,
  • Akira Matsuishi,
  • Ryo Kanoda,
  • Yuya Maruyama,
  • Hiroya Suzuki,
  • Hirokazu Okayama,
  • Motonobu Saito,
  • Kosaku Mimura,
  • Azuma Nirei,
  • Tomohiro Kikuchi,
  • Hiroyuki Hanayama,
  • Zenichiro Saze,
  • Tomoyuki Momma,
  • Kyoko Nishiyama,
  • Tatsuo Suzutani,
  • Koji Kono

摘要

Background

Intratumoral Fusobacterium nucleatum (Fn) infection is closely associated with poor prognosis in esophageal cancer (EC) due to its impact on the tumor microenvironment (TME). The tumor cell-intrinsic cyclic GMP–AMP synthase (cGAS)–stimulator of interferon genes (STING) pathway is critical for regulating immune cell activation in the TME. However, the link between intratumoral Fn infection and the activation of the cGAS–STING pathway in tumor cells, as well as its effects on EC progression, remains largely unknown.

Methods

In the present study, we investigated the impact of intratumoral Fn infection on the activation of the tumor cell-intrinsic cGAS–STING pathway and EC progression by analyzing our own EC cohort and performing in vitro experiments using co-cultures of EC-cell lines and Fn.

Results

The expression of tumor cell-intrinsic STING was significantly associated with worse prognosis in Fn-high EC patients. Exposure to Fn significantly activated the STING pathway in EC cells. RNA-seq analysis revealed that exposure to Fn markedly activated cytokine–chemokine-related signaling pathways and induced the expression of several cytokines and chemokines in STING-expressing EC cells. Among the differentially expressed cytokine and chemokine genes in EC cells co-cultured with Fn, analysis of TCGA datasets demonstrated that the expression of CCL20, CXCL10, and CSF2 may be associated with poor prognosis in EC patients.

Conclusion

We revealed that the activation of the STING signaling pathway and the subsequent expression of cytokines and chemokines in EC cells induced by Fn infection may be closely associated with poor prognosis in EC patients.