F. nucleatum drives immunosuppression and metastasis in TNBC

Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype characterized by limited targeted treatment options, a high propensity for distant metastasis and variable responses to immune checkpoint blockade. Increasing evidence indicates that the tumor microbiome can influence cancer progression and therapeutic responses, yet the mechanisms through which intratumoral bacteria reshape the TNBC microenvironment remain poorly understood. Fusobacterium nucleatum, a Gram-negative anaerobic bacterium associated with several cancers, has been detected in breast tumors and linked to metastatic progression, but its contribution to metabolic and immune regulation in TNBC has remained unclear.

A new study in Genes & Diseases by researchers from Chongqing Medical University, Chongqing Hospital of Traditional Chinese Medicine, and The First Affiliated Hospital of Chongqing Medical University identified F. nucleatum as a key driver of tryptophan metabolic reprogramming, immunosuppression and lung metastasis in TNBC.

Fluorescence in situ hybridization (FISH) analysis using specific probes, combined with confocal microscopy of human breast cancer tissues, revealed that F. nucleatum was more abundant in TNBC than in estrogen receptor-positive or HER2-positive breast cancer and was enriched in metastatic tumors. Experimental studies further demonstrated that F. nucleatum adhered to and invaded TNBC cells and promoted tumor growth, invasion and pulmonary metastasis in mouse models. These effects were accompanied by reduced infiltration and functional activity of CD8+ T cells, indicating that F. nucleatum contributes to an immunosuppressive tumor microenvironment.

Transcriptomic analysis revealed activation of tryptophan metabolism and JAK–STAT signaling following F. nucleatum exposure, with marked induction of IL4I1, a tryptophan-metabolizing enzyme distinct from the classical enzymes IDO1 and TDO2. IL4I1 was elevated in breast cancer tissues and associated with poorer survival in TNBC. Genetic suppression of IL4I1 substantially reduced F. nucleatum-induced invasion, tumor growth, and lung metastasis, while restoring CD8+ T-cell infiltration and antitumor activity, identifying IL4I1 as a critical downstream mediator of the bacterium's effects.

Mechanistically, the study demonstrated that F. nucleatum promotes IL4I1 expression through the IL20–JAK–STAT4 signaling axis. F. nucleatum increased IL20 secretion by TNBC cells, which activated JAK–STAT4 signaling and enhanced IL4I1 transcription. Promoter analyses and ChIP assays established STAT4 as a direct transcriptional regulator of IL4I1. Pharmacological inhibition of JAK–STAT4 signaling reduced IL4I1 expression and suppressed the pro-invasive effects of F. nucleatum.

LC-MS/MS further demonstrated that F. nucleatum enhanced the production of IL4I1-derived tryptophan metabolites, including indole-3-pyruvate (I3P), indole-3-acetic acid, indole-3-aldehyde and indole-3-lactic acid. I3P activated the aryl hydrocarbon receptor (AHR) pathway, promoted TNBC cell invasion and increased PD-L1 expression, providing a mechanistic link between bacterial metabolic reprogramming, tumor aggressiveness and immune escape. In mouse models, F. nucleatum also impaired the antitumor effects of anti-PD-1 therapy, increased tumor progression and lung metastasis, and reduced CD8+ T-cell activity.

Overall, this study establishes an IL20–JAK–STAT4–IL4I1 cascade through which F. nucleatum reprograms tryptophan metabolism to promote immune evasion and metastatic progression in TNBC. These findings identify IL4I1 as a potentially actionable immunometabolic checkpoint and provide a mechanistic framework linking the tumor microbiome with metabolic and immune determinants of immunotherapy resistance.

Reference
Title of the original paper: Fusobacterium nucleatum-mediated tryptophan metabolic reprogramming facilitates immunosuppression and metastasis in triple-negative breast cancer
Journal: Genes & Diseases
Genes & Diseases is a journal for molecular and translational medicine. The journal primarily focuses on publishing investigations on the molecular bases and experimental therapeutics of human diseases. Publication formats include full length research article, review article, short communication, correspondence, perspectives, commentary, views on news, and research watch.
DOI: https://doi.org/10.1016/j.gendis.2026.102260

Funding Information:
National Natural Science Foundation of China (No. 82073255)
Chongqing Talents Program for Innovative and Entrepreneurial Pioneers (China) (No. cstc2024ycjh-bgzxm0176)
Foundation of Chongqing Municipal Education Commission (China) (No. HZ2021006)
Chongqing Medical University Outstanding Talents Project (China) (No. BJRC202414)

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Genes & Diseases publishes rigorously peer-reviewed and high quality original articles and authoritative reviews that focus on the molecular bases of human diseases. Emphasis is placed on hypothesis-driven, mechanistic studies relevant to pathogenesis and/or experimental therapeutics of human diseases. The journal has worldwide authorship, and a broad scope in basic and translational biomedical research of molecular biology, molecular genetics, and cell biology, including but not limited to cell proliferation and apoptosis, signal transduction, stem cell biology, developmental biology, gene regulation and epigenetics, cancer biology, immunity and infection, neuroscience, disease-specific animal models, gene and cell-based therapies, and regenerative medicine.
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F. nucleatum promotes IL20 secretion and promotes IL4I1 expression through the IL20/JAK/STAT4 signaling axis in TNBC cells. Moreover, F. nucleatum-mediated tryptophan metabolic reprogramming up-regulates PD-L1 expression in TNBC cells, thereby promoting immunosuppression and lung metastasis.
(A) Schematic diagram of animal studies. BALB/c mice were implanted with 4T1 mouse breast cancer cells on day 0 and intratumorally injected with F. nucleatum or PBS from day 7 to the end of the experiment. (B) Representative images of tumors under different treatments (n = 5). (C) Tumor weight of mice in each group (n = 5). (D) Number of metastatic nodules in the lungs in each group (n = 5). (E) Hematoxylin–eosin staining of the lung metastatic area. (F) Representative images of immunohistochemistry-stained E-Cadherin and N-Cadherin in paraffin-embedded tumor tissues. Cell nuclei were stained with hematoxylin. Scale bar, 40 μm. (G) Representative images of Transwell assays. Scale bar, 50 μm. (H) Representative flow cytometry data of CD8+ T cells in tumor tissues. (I) Quantification of CD8+ T cells in tumor tissues. (J) Representative flow cytometry data of Ki67+CD8+ T cells in tumor tissues. (K) Quantification of Ki67+CD8+ T cells in tumor tissues. (L) Representative flow cytometry data of IFN-γ+CD8+ T cells in tumor tissues. (M) Quantification of IFN-γ+CD8+ T cells in tumor tissues. All data are presented as the mean ± standard deviation of triplicate experiments. P-values were analyzed by a two-tailed unpaired Student's t-test. P-values less than 0.05 were considered statistically significant. ∗P < 0.05, ∗∗P < 0.01, ∗∗∗P < 0.001, and ∗∗∗∗P < 0.0001.
(A) Schematic diagram of tryptophan metabolism. (B) The expression of IL4I1 was measured by Western blotting in TNBC cells treated with F. nucleatum or F. nucleatum plus ruxolitinib. (C) I3P in supernatants of MDA-MB-231 cells. (D) IAA in supernatants and intracellular of MDA-MB-231 cells. (E) I3A in supernatants of MDA-MB-231 cells. (F) ILA in supernatants and intracellular of MDA-MB-231 cells. (G) The mRNA levels of AHR downstream genes were measured by quantitative PCR analysis in MDA-MB-231 cells and BT549 cells treated with control and I3P. (H) Representative images of Transwell assays. Scale bar, 50 μm. (I) The expression of PD-L1 was measured by Western blotting in TNBC cells treated with control or 25 μM I3P for 4 h. All data are presented as the mean ± standard deviation of triplicate experiments. P-values were analyzed by one-way ANOVA (C–F) or two-tailed unpaired Student's t-test (G, H). P-values less than 0.05 were considered statistically significant. ∗P < 0.05, ∗∗P < 0.01, ∗∗∗P < 0.001, and ∗∗∗∗P < 0.0001.

09.09.2026 Compuscript Ltd

Regions: Europe, Ireland, Asia, China

Keywords: Science, Life Sciences

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