F. nucleatum facilitates oral squamous cell carcinoma progression via GLUT1-driven lactate production

Sep 24, 2026

Tumor-resident microbiota shapes cancer microenvironments, yet the contribution of Fusobacterium nucleatum to oral squamous cell carcinoma (OSCC) progression remains unclear. Bioinformatics and clinical sample analyses, combined with xenograft models, metabolic screening, and RNA sequencing, were used to define mechanisms. F. nucleatum accumulates at OSCC invasive margins and promotes tumor-associated macrophage formation through GalNAc-mediated autophagy-TBC1D5 signaling, driving GLUT1 aggregation and extracellular lactate deposition. Inhibiting GalNAc and GLUT1 reduces TAMs and restrains OSCC progression.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages20

Reading Time50 min

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Articles F. nucleatum facilitates oral squamous cell carcinoma progression via GLUT1-driven lactate production Jiwei Sun,a,b,c,f Qingming Tang,a,b,c,f Shaoling Yu,a,b,c Mengru Xie,a,b,c Wenhao Zheng,a,b,c Guangjin Chen,a,b,c Ying Yin,a,b,c Xiaofei Huang,a,b,c Keqi Wo,a,b,c Haoqi Lei,a,b,c Junyuan Zhang,a,b,c Qian Wan,d,e and Lili Chena,b,c,∗ aDepartment of Stomatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China bSchool of Stomatology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China cHubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, 430022, China dHubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan, 430030, Hubei, China eInstitute of Brain Research, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan, 430030, Hubei, China Summary Background Tumor-resident microbiota has been documented for various cancer types. Oral squamous cell carcinoma (OSCC) is also enriched with microbiota, while the signiﬁcance of microbiota in shaping the OSCC microenvironment remains elusive. Methods We used bioinformatics and clinical sample analysis to explore relationship between F. nucleatum and OSCC progression. Xenograft tumor model, metabolic screening and RNA sequencing were performed to elucidate mechanisms of pro-tumor role of F. nucleatum. Findings We show that a major protumorigenic bacterium, F. nucleatum, accumulates in invasive margins ofOSCC tissues and drives tumor-associated macrophages (TAMs) formation. The mechanistic dissection shows that OSCCresident F. nucleatum triggers the GalNAc-Autophagy-TBC1D5 signaling, leading to GLUT1 aggregation in the plasma membrane and the deposition of extracellular lactate. Simultaneous functional inhibition of GalNAc and GLUT1 efﬁciently reduces TAMs formation and restrains OSCC progression. Interpretation These ﬁndings suggest that tumor-resident microbiota affects the immunomodulatory and protumorigenic microenvironment via modulating glycolysis and extracellular lactate deposition. The targeted intervention of this process could provide a distinct clinical strategy for patients with advanced OSCC. Funding This work was supported by the National Natural Science Foundation of China for Key Program Projects (82030070, to LC) and Distinguished Young Scholars (31725011, to LC), as well as Innovation Team Project of Hubei Province (2020CFA014, to LC) . Copyright © 2023 The Author(s) . Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license ([http://creativecommons.org/licenses/by-nc-nd/4.0/](http://creativecommons.org/licenses/by-nc-nd/4.0/)). Keywords: Oral squamous cell carcinoma; F. nucleatum; Tumor-associated macrophage; GLUT1; Autophagy Introduction Oral squamous cell carcinoma (OSCC) is a prevalent subtype of head and neck squamous cell carcinoma (HNSCC) .1–3 Despite progress in the diagnosis and treatment of OSCC, the 5-year survival rate remains low due to metastasis or recurrence.4 , 5 Cohort studies have suggested that, in addition to the genetic, epigenetic, and stromal microenvironment elements, the features of the microbiota within tissues are associated with the hallmarks of cancer, including risks, pathological types, and prognosis.6–10 Likewise, given that OSCC originates in the microbiota-enriched oral cavity, the microbiota emerges as a non-negligible potential mediator regulating OSCC progression.11–14 F. nucleatum is a gram-negative anaerobic bacterium and has been suggested as a major protumorigenic bacterium compared with other oral bacteria.15 , 16 However, as the constituent species of OSCC microbiota, how F. nucleatum affects the progression of OSCC remains largely unexplored. *Corresponding author. Department of Stomatology, U

FAQs

What role does F. nucleatum play in OSCC progression?

F. nucleatum accumulates in invasive margins of OSCC tissues and drives tumor-associated macrophage (TAM) formation, promoting OSCC progression.

How does F. nucleatum regulate lactate production and GLUT1?

OSCC-resident F. nucleatum triggers GalNAc-autophagy-TBC1D5 signaling, leading to GLUT1 aggregation in the plasma membrane and extracellular lactate deposition.

What therapeutic strategy does the study suggest?

Simultaneous functional inhibition of GalNAc and GLUT1 efficiently reduces TAM formation and restrains OSCC progression, indicating a targeted clinical intervention potential.

Sep 24, 2026

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