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. 2025 Apr;22(2):239-249.
doi: 10.1007/s10388-025-01112-z. Epub 2025 Feb 14.

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

Shotaro Nakajima  1   2 , Katsuharu Saito  3 , Satoshi Fukai  3 , Mei Sakuma  3 , Akira Matsuishi  3 , Ryo Kanoda  3 , Yuya Maruyama  3 , Hiroya Suzuki  3 , Hirokazu Okayama  3 , Motonobu Saito  3 , Kosaku Mimura  3   4 , Azuma Nirei  3 , Tomohiro Kikuchi  3 , Hiroyuki Hanayama  3 , Zenichiro Saze  3 , Tomoyuki Momma  3 , Kyoko Nishiyama  5 , Tatsuo Suzutani  5 , Koji Kono  6   7
Affiliations

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

Shotaro Nakajima et al. Esophagus. 2025 Apr.

Abstract

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.

Keywords: Fusobacterium nucleatum; Esophageal cancer; Tumor cell-intrinsic STING pathway; Tumor microenvironment.

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Conflict of interest statement

Declarations. Ethical statement: This study was approved by the Institutional Ethical Committee of Fukushima Medical University (Approval No. 2329), and all procedures were conducted in accordance with the Declaration of Helsinki. Conflict of interest: Authors 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, and Koji Kono declare that they have no conflict of interest. Consent to paticipate: Written informed consent was obtained from all patients for the use of tissue specimens and clinical data.

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