Fusobacterium nucleatum in cancer: Interactions with microbiota, tumour colonisation and cancer progression

Abstract

Background: Growing evidence from multi-cancer cohort studies has positioned the oral pathobiont Fusobacterium nucleatum (F. nucleatum) as an emerging microbial contributor to cancer progression. Increased intratumoral abundance of F. nucleatum has been reported in colorectal, breast, esophageal, pancreatic, oral, and gastric cancers and is frequently associated with adverse clinicopathological features, treatment resistance, metastatic behavior, and poor prognosis. Advances in microbiome profiling, spatial analysis, and single-cell technologies have begun to reveal how F. nucleatum colonizes tumors and interacts with host cells and tumor-associated microbial communities.

Main body: This review summarizes current evidence regarding the tumor-associated activities of F. nucleatum, with emphasis on its routes of tumor entry, spatiotemporal colonization patterns, adhesion- and glycan-dependent tropism, polymicrobial niche formation, and crosstalk with cancer cells and immune components. We discuss how F. nucleatum promotes oncogenic signaling, inflammatory amplification, genomic and epigenetic reprogramming, epithelial–mesenchymal transition, metastatic dissemination, immune evasion, and therapy adaptation. Particular attention is given to its context-dependent effects on chemotherapy, radiotherapy, and immunotherapy responses, as well as emerging strategies aimed at detecting or selectively targeting intratumoral F. nucleatum.

Conclusion: F. nucleatum represents both a biomarker-associated organism and a potentially modifiable component of the tumor microenvironment. Defining its strain-level heterogeneity, spatial ecology, and therapy-specific functions will be essential for translating microbiome-guided precision oncology from mechanistic insight into clinical application.

Key points:

Keywords

chemoresistance / Fusobacterium nucleatum / immune evasion / targeted microbiome therapy / tumour microbiome / tumour microenvironment

References

[1] Rous P. A sarcoma of the fowl transmissible by an agent separable from the tumor cells. J Exp Med. 1911; 13(4): 397-411.

[2] Epstein M, Achong B, Barr Y. Virus particles in cultured lymphoblasts from Burkitt's lymphoma. Lancet. 1964; 1(7335): 702-703.

[3] Zapatka M, Borozan I, Brewer DS, et al. The landscape of viral associations in human cancers. Nat Genet. 2020; 52(3): 320-330.

[4] Loughlin KR. Coley: his hypothesis, his toxin, and the birth of immunotherapy. Urol Clin North Am. 2020; 47(4): 413-417.

[5] Zhou S, Gravekamp C, Bermudes D, Liu K. Tumour-targeting bacteria engineered to fight cancer. Nat Rev Cancer. 2018; 18(12): 727-743.

[6] Starnes C. Coley's toxins in perspective. Nature. 1992; 357(6373): 11-12.

[7] Sepich-Poore GD, Zitvogel L, Straussman R, Hasty J, Wargo JA, Knight R. The microbiome and human cancer. Science. 2021; 371(6536):eabc4552.

[8] Lenis AT, Lec PM, Chamie K, MSHS M. Bladder cancer: a review. JAMA. 2020; 324(19): 1980-1991.

[9] Pettenati C, Ingersoll M. Mechanisms of BCG immunotherapy and its outlook for bladder cancer. Nat Rev Urol. 2018; 15(10): 615-625.

[10] Parsonnet J, Friedman GD, Vandersteen DP, et al. Helicobacter pylori infection and the risk of gastric carcinoma. N Engl J Med. 1991; 325(16): 1127-1131.

[11] Dudgeon L, Dunkley E. The micrococcus neoformans: its cultural characters and pathogenicity and the results of the estimation of the opsonic and agglutinative properties of the serum of patients suffering from malignant disease on this organism and on the staphylococcus albus. J Hyg (Lond). 1907; 7(1): 13-21.

[12] Uemura N, Okamoto S, Yamamoto S, et al. Helicobacter pylori infection and the development of gastric cancer. N Engl J Med. 2001; 345(11): 784-789.

[13] Amieva M. Pathobiology of Helicobacter pylori-induced gastric cancer. Gastroenterology. 2016; 150(1): 64-78.

[14] Scott AJ, Alexander JL, Merrifield CA, et al. International cancer microbiome consortium consensus statement on the role of the human microbiome in carcinogenesis. Gut. 2019; 68(9): 1624-1632.

[15] Tjalsma H, Boleij A, Marchesi JR, Dutilh BE. A bacterial driver-passenger model for colorectal cancer: beyond the usual suspects. Nat Rev Microbiol. 2012; 10(8): 575-582.

[16] Jin Y, Dong H, Xia L, et al. The diversity of gut microbiome is associated with favorable responses to anti-programmed death 1 immunotherapy in Chinese patients with NSCLC. J Thorac Oncol. 2019; 14(8): 1378-1389.

[17] Nejman D, Livyatan I, Fuks G, et al. The human tumor microbiome is composed of tumor type-specific intracellular bacteria. Science. 2020; 368(6494): 973-980.

[18] Livyatan I, Nejman D, Shental N, Straussman R. Characterization of the human tumor microbiome reveals tumor-type specific intra-cellular bacteria. Oncoimmunology. 2020; 9(1):1800957.

[19] Helmink BA, Khan MAW, Hermann A, Gopalakrishnan V, Wargo JA. The microbiome, cancer, and cancer therapy. Nat Med. 2019; 25(3): 377-388.

[20] Mc C. Enterococcal endocarditis associated with carcinoma of the sigmoid; report of a case. J Med Assoc State Ala. 1951; 21(6): 162-166.

[21] Poore GD, Kopylova E, Zhu Q, et al. Microbiome analyses of blood and tissues suggest cancer diagnostic approach. Nature. 2020; 579(7800): 567-574.

[22] Galeano Niño JL, Wu H, LaCourse KD, et al. Effect of the intratumoral microbiota on spatial and cellular heterogeneity in cancer. Nature. 2022; 611(7937): 810-817.

[23] Kalaora S, Nagler A, Nejman D, et al. Identification of bacteria-derived HLA-bound peptides in melanoma. Nature. 2021; 592(7852): 138-143.

[24] Wang N, Fang J. Fusobacterium nucleatum, a key pathogenic factor and microbial biomarker for colorectal cancer. Trends Microbiol. 2023; 31(2): 159-172.

[25] Whitmore S, Lamont R. Oral bacteria and cancer. PLoS Pathog. 2014; 10(3):e1003933.

[26] Fitzsimonds Z, Rodriguez-Hernandez C, Bagaitkar J, Lamont R. From beyond the pale to the pale riders: the emerging association of bacteria with oral cancer. J Dent Res. 2020; 99(6): 604-612.

[27] Hajishengallis G, Chavakis T. Local and systemic mechanisms linking periodontal disease and inflammatory comorbidities. Nat Rev Immunol. 2021; 21(7): 426-440.

[28] Brennan CA, Clay SL, Lavoie SL, et al. Fusobacterium nucleatum drives a pro-inflammatory intestinal microenvironment through metabolite receptor-dependent modulation of IL-17 expression. Gut Microbes. 2021; 13(1):1987780.

[29] Song B, Xian W, Sun Y, et al. Akkermansia muciniphila inhibited the periodontitis caused by Fusobacterium nucleatum. NPJ Biofilms Microbiomes. 2023; 9(1): 49.

[30] Didilescu AC, Rusu D, Anghel A, et al. Investigation of six selected bacterial species in endo-periodontal lesions. Int Endod J. 2012; 45(3): 282-293.

[31] Arenas Rodrigues VA, de Avila ED, Nakano V, Avila-Campos MJ. Qualitative, quantitative and genotypic evaluation of Aggregatibacter actinomycetemcomitans and Fusobacterium nucleatum isolated from individuals with different periodontal clinical conditions. Anaerobe. 2018; 52: 50-58.

[32] Chaushu S, Wilensky A, Gur C, et al. Direct recognition of Fusobacterium nucleatum by the NK cell natural cytotoxicity receptor NKp46 aggravates periodontal disease. PLoS Pathog. 2012; 8(3):e1002601.

[33] Kostic AD, Gevers D, Pedamallu CS, et al. Genomic analysis identifies association of Fusobacterium with colorectal carcinoma. Genome Res. 2012; 22(2): 292-298.

[34] Castellarin M, Warren RL, Freeman JD, et al. Fusobacterium nucleatum infection is prevalent in human colorectal carcinoma. Genome Res. 2012; 22(2): 299-306.

[35] Mitsuhashi K, Nosho K, Sukawa Y, et al. Association of Fusobacterium species in pancreatic cancer tissues with molecular features and prognosis. Oncotarget. 2015; 6(9): 7209-7220.

[36] Gaiser RA, Halimi A, Alkharaan H, et al. Enrichment of oral microbiota in early cystic precursors to invasive pancreatic cancer. Gut. 2019; 68(12): 2186-2194.

[37] Yamamura K, Baba Y, Nakagawa S, et al. Human microbiome Fusobacterium nucleatum in esophageal cancer tissue is associated with prognosis. Clin Cancer Res. 2016; 22(22): 5574-5581.

[38] Yamamura K, Izumi D, Kandimalla R, et al. Intratumoral Fusobacterium nucleatum levels predict therapeutic response to neoadjuvant chemotherapy in esophageal squamous cell carcinoma. Clin Cancer Res. 2019; 25(20): 6170-6179.

[39] Hieken TJ, Chen J, Hoskin TL, et al. The microbiome of aseptically collected human breast tissue in benign and malignant disease. Sci Rep. 2016; 6:30751.

[40] Parhi L, Alon-Maimon T, Sol A, et al. Breast cancer colonization by Fusobacterium nucleatum accelerates tumor growth and metastatic progression. Nat Commun. 2020; 11(1): 3259.

[41] Mima K, Nishihara R, Qian ZR, et al. Fusobacterium nucleatum in colorectal carcinoma tissue and patient prognosis. Gut. 2016; 65(12): 1973-1980.

[42] Zhang L, Leng X, Qi J, et al. The adhesin RadD enhances Fusobacterium nucleatum tumour colonization and colorectal carcinogenesis. Nat Microbiol. 2024; 9(9): 2292-2307.

[43] Rubinstein MR, Baik JE, Lagana SM, et al. Fusobacterium nucleatum promotes colorectal cancer by inducing Wnt/beta-catenin modulator annexin A1. EMBO Rep. 2019; 20(4):e47638.

[44] Rubinstein M, Wang X, Liu W, Hao Y, Cai G, Han Y. Fusobacterium nucleatum promotes colorectal carcinogenesis by modulating E-cadherin/beta-catenin signaling via its FadA adhesin. Cell Host Microbe. 2013; 14(2): 195-206.

[45] Kostic A, Chun E, Robertson L, et al. Fusobacterium nucleatum potentiates intestinal tumorigenesis and modulates the tumor-immune microenvironment. Cell Host Microbe. 2013; 14(2): 207-215.

[46] Bullman S, Pedamallu CS, Sicinska E, et al. Analysis of Fusobacterium persistence and antibiotic response in colorectal cancer. Science. 2017; 358(6369): 1443-1448.

[47] Yang Y, Weng W, Peng J, et al. Fusobacterium nucleatum increases proliferation of colorectal cancer cells and tumor development in mice by activating Toll-like receptor 4 signaling to nuclear factor-kappab, and up-regulating expression of microRNA-21. Gastroenterology. 2017; 152(4): 851-866 e24.

[48] Dadashi M, Hajikhani B, Faghihloo E, et al. Proliferative effect of FadA recombinant protein from fusobacterium nucleatum on SW480 colorectal cancer cell line. Infect Disord Drug Targets. 2021; 21(4): 623-628.

[49] Yu T, Guo F, Yu Y, et al. Fusobacterium nucleatum promotes chemoresistance to colorectal cancer by modulating autophagy. Cell. 2017; 170(3): 548-563 e16.

[50] Allen-Vercoe E, Strauss J, Chadee K. Fusobacterium nucleatum: an emerging gut pathogen?. Gut Microbes. 2011; 2(5): 294-298.

[51] Manson McGuire A, Cochrane K, Griggs AD, et al. Evolution of invasion in a diverse set of Fusobacterium species. mBio. 2014; 5(6):e01864.

[52] Holt R, Cochrane K. Tumor potentiating mechanisms of fusobacterium nucleatum, a multifaceted microbe. Gastroenterology. 2017; 152(4): 694-696.

[53] Ponath F, Zhu Y, Cosi V, Vogel J. Expanding the genetic toolkit helps dissect a global stress response in the early-branching species Fusobacterium nucleatum. Proc Natl Acad Sci U S A. 2022; 119(40):e2201460119.

[54] Zepeda-Rivera M, Minot SS, Bouzek H, et al. A distinct Fusobacterium nucleatum clade dominates the colorectal cancer niche. Nature. 2024; 628(8007): 424-432.

[55] Jiang S, Xie Y, Xiao X, et al. Fusobacterium nucleatum-derived succinic acid induces tumor resistance to immunotherapy in colorectal cancer. Cell Host Microbe. 2023; 31(5): 781-797 e9.

[56] Turnbaugh PJ, Ley RE, Hamady M, Fraser-Liggett CM, Knight R, Gordon JI. The human microbiome project. Nature. 2007; 449(7164): 804-810.

[57] Li Z, Shi C, Zheng J, et al. Fusobacterium nucleatum predicts a high risk of metastasis for esophageal squamous cell carcinoma. BMC Microbiol. 2021; 21(1): 301.

[58] Kong C, Yan X, Zhu Y, et al. Fusobacterium nucleatum promotes the development of colorectal cancer by activating a cytochrome P450/Epoxyoctadecenoic acid axis via TLR4/Keap1/NRF2 signaling. Cancer Res. 2021; 81(17): 4485-4498.

[59] Chen G, Gao C, Jiang S, et al. Fusobacterium nucleatum outer membrane vesicles activate autophagy to promote oral cancer metastasis. J Adv Res. 2024; 56: 167-179.

[60] Zhang T, Li Y, Zhai E, et al. Intratumoral fusobacterium nucleatum recruits tumor-associated neutrophils to promote gastric cancer progression and immune evasion. Cancer Res. 2025; 85(10): 1819-1841.

[61] Qu X, Yin F, Pei M, et al. Modulation of intratumoral fusobacterium nucleatum to enhance sonodynamic therapy for colorectal cancer with reduced phototoxic skin injury. ACS Nano. 2023; 17(12): 11466-11480.

[62] Wu J, Li Q, Fu X. Fusobacterium nucleatum contributes to the carcinogenesis of colorectal cancer by inducing inflammation and suppressing host immunity. Transl Oncol. 2019; 12(6): 846-851.

[63] Yin H, Miao Z, Wang L, et al. Fusobacterium nucleatum promotes liver metastasis in colorectal cancer by regulating the hepatic immune niche and altering gut microbiota. Aging (Albany NY). 2022; 14(4): 1941-1958.

[64] Wang Y, Gao W, Shi X, et al. Chemotherapy drugs induce pyroptosis through caspase-3 cleavage of a gasdermin. Nature. 2017; 547(7661): 99-103.

[65] Li Y, Hively W, Varmus H. Use of MMTV-Wnt-1 transgenic mice for studying the genetic basis of breast cancer. Oncogene. 2000; 19(8): 1002-1009.

[66] Hayashi M, Ikenaga N, Nakata K, et al. Intratumor Fusobacterium nucleatum promotes the progression of pancreatic cancer via the CXCL1-CXCR2 axis. Cancer Sci. 2023; 114(9): 3666-3678.

[67] Chen S, Su T, Zhang Y, et al. Fusobacterium nucleatum promotes colorectal cancer metastasis by modulating KRT7-AS/KRT7. Gut Microbes. 2020; 11(3): 511-525.

[68] Li X, Ma Y, Xin Y, Ma F, Gao H. Tumor-targeting nanoassembly for enhanced colorectal cancer therapy by eliminating intratumoral Fusobacterium nucleatum. ACS Appl Mater Interfaces. 2023; 15(11): 14164-14172.

[69] Tong Y, Lu G, Wang Z, Hao S, Zhang G, Sun H. Tubeimuside I improves the efficacy of a therapeutic Fusobacterium nucleatum dendritic cell-based vaccine against colorectal cancer. Front Immunol. 2023; 14:1154818.

[70] Fu A, Yao B, Dong T, et al. Tumor-resident intracellular microbiota promotes metastatic colonization in breast cancer. Cell. 2022; 185(8): 1356-1372 e26.

[71] Walker S, Tangney M, Claesson M. Sequence-based characterization of intratumoral bacteria-a guide to best practice. Front Oncol. 2020; 10: 179.

[72] Azevedo M, Pina-Vaz C, Baltazar F. Microbes and cancer: friends or faux?. Int J Mol Sci. 2020; 21(9): 3115.

[73] Wong-Rolle A, Wei HK, Zhao C, Jin C. Unexpected guests in the tumor microenvironment: microbiome in cancer. Protein Cell. 2021; 12(5): 426-435.

[74] Garrett W. Cancer and the microbiota. Science. 2015; 348(6230): 80-86.

[75] Komiya Y, Shimomura Y, Higurashi T, et al. Patients with colorectal cancer have identical strains of Fusobacterium nucleatum in their colorectal cancer and oral cavity. Gut. 2019; 68(7): 1335-1337.

[76] Abed J, Maalouf N, Manson AL, et al. Colon cancer-associated fusobacterium nucleatum may originate from the oral cavity and reach colon tumors via the circulatory system. Front Cell Infect Microbiol. 2020; 10: 400.

[77] Riquelme E, Maitra A, McAllister F. Immunotherapy for pancreatic cancer: more than just a gut feeling. Cancer Discov. 2018; 8(4): 386-388.

[78] Charlson ES, Bittinger K, Haas AR, et al. Topographical continuity of bacterial populations in the healthy human respiratory tract. Am J Respir Crit Care Med. 2011; 184(8): 957-963.

[79] Shi Y, Zheng W, Yang K, et al. Intratumoral accumulation of gut microbiota facilitates CD47-based immunotherapy via STING signaling. J Exp Med. 2020; 217(5):e20192282.

[80] Silver J, Martin A, McBride B. Experimental transient bacteraemias in human subjects with varying degrees of plaque accumulation and gingival inflammation. J Clin Periodontol. 1977; 4(2): 92-99.

[81] Parahitiyawa NB, Jin LJ, Leung WK, Yam WC, Samaranayake LP. Microbiology of odontogenic bacteremia: beyond endocarditis. Clin Microbiol Rev. 2009; 22(1): 46-64. Table of Contents.

[82] Hajishengallis G. Periodontitis: from microbial immune subversion to systemic inflammation. Nat Rev Immunol. 2015; 15(1): 30-44.

[83] Ishikawa M, Yoshida K, Okamura H, et al. Oral Porphyromonas gingivalis translocates to the liver and regulates hepatic glycogen synthesis through the Akt/GSK-3beta signaling pathway. Biochim Biophys Acta. 2013; 1832(12): 2035-2043.

[84] Lewis K. Persister cells, dormancy and infectious disease. Nat Rev Microbiol. 2007; 5(1): 48-56.

[85] del Pozo J, Patel R. The challenge of treating biofilm-associated bacterial infections. Clin Pharmacol Ther. 2007; 82(2): 204-209.

[86] Mahendra J, Mahendra L, Kurian VM, Jaishankar K, Mythilli R. Prevalence of periodontal pathogens in coronary atherosclerotic plaque of patients undergoing coronary artery bypass graft surgery. J Maxillofac Oral Surg. 2009; 8(2): 108-113.

[87] Gao S, Li S, Ma Z, et al. Presence of Porphyromonas gingivalis in esophagus and its association with the clinicopathological characteristics and survival in patients with esophageal cancer. Infect Agent Cancer. 2016; 11: 3.

[88] Casasanta MA, Yoo CC, Udayasuryan B, et al. Fusobacterium nucleatum host-cell binding and invasion induces IL-8 and CXCL1 secretion that drives colorectal cancer cell migration. Sci Signal. 2020; 13(641):eaba9157.

[89] Chen Y, Chen Y, Zhang J, et al. Fusobacterium nucleatum promotes metastasis in colorectal cancer by activating autophagy signaling via the upregulation of CARD3 expression. Theranostics. 2020; 10(1): 323-339.

[90] Abed J, Emgård J, Zamir G, et al. Fap2 mediates Fusobacterium nucleatum colorectal adenocarcinoma enrichment by binding to tumor-expressed Gal-GalNAc. Cell Host Microbe. 2016; 20(2): 215-225.

[91] Chen Y, Peng Y, Yu J, et al. Invasive Fusobacterium nucleatum activates beta-catenin signaling in colorectal cancer via a TLR4/P-PAK1 cascade. Oncotarget. 2017; 8(19): 31802-31814.

[92] Hashemi Goradel N, Heidarzadeh S, Jahangiri S, et al. Fusobacterium nucleatum and colorectal cancer: a mechanistic overview. J Cell Physiol. 2019; 234(3): 2337-2344.

[93] Kvich L, Fritz BG, Zschach H, et al. Biofilms and core pathogens shape the tumor microenvironment and immune phenotype in colorectal cancer. Gut Microbes. 2024; 16(1):2350156.

[94] Sakanaka A, Kuboniwa M, Shimma S, et al. Fusobacterium nucleatum metabolically integrates commensals and pathogens in oral biofilms. mSystems. 2022; 7(4):e0017022.

[95] Drewes JL, White JR, Dejea CM, et al. Erratum: author correction: high-resolution bacterial 16S rRNA gene profile meta-analysis and biofilm status reveal common colorectal cancer consortia. NPJ Biofilms Microbiomes. 2019; 5(1): 2.

[96] Xia X, Wu WKK, Wong SH, et al. Bacteria pathogens drive host colonic epithelial cell promoter hypermethylation of tumor suppressor genes in colorectal cancer. Microbiome. 2020; 8(1): 108.

[97] Weisenberger DJ, Siegmund KD, Campan M, et al. CpG island methylator phenotype underlies sporadic microsatellite instability and is tightly associated with BRAF mutation in colorectal cancer. Nat Genet. 2006; 38(7): 787-793.

[98] Koi M, Okita Y, M Carethers J. Fusobacterium nucleatum infection in colorectal cancer: linking inflammation, DNA mismatch repair and genetic and epigenetic alterations. J Anus Rectum Colon. 2018; 2(2): 37-46.

[99] Kelly D, Yang L, Pei Z. Gut microbiota, fusobacteria, and colorectal cancer. Diseases. 2018; 6(4): 109.

[100] Ito M, Kanno S, Nosho K, et al. Association of Fusobacterium nucleatum with clinical and molecular features in colorectal serrated pathway. Int J Cancer. 2015; 137(6): 1258-1268.

[101] Tahara T, Yamamoto E, Suzuki H, et al. Fusobacterium in colonic flora and molecular features of colorectal carcinoma. Cancer Res. 2014; 74(5): 1311-1318.

[102] Lee D, Han S, Kang J, et al. Association between Fusobacterium nucleatum, pathway mutation, and patient prognosis in colorectal cancer. Ann Surg Oncol. 2018; 25(11): 3389-3395.

[103] Guo P, Tian Z, Kong X, et al. FadA promotes DNA damage and progression of Fusobacterium nucleatum-induced colorectal cancer through up-regulation of chk2. J Exp Clin Cancer Res. 2020; 39(1): 202.

[104] Geng F, Zhang Y, Lu Z, Zhang S, Pan Y. Fusobacterium nucleatum caused DNA damage and promoted cell proliferation by the Ku70/p53 pathway in oral cancer cells. DNA Cell Biol. 2020; 39(1): 144-151.

[105] Sayed IM, Chakraborty A, Abd El-Hafeez AA, et al. The DNA glycosylase NEIL2 suppresses fusobacterium-infection-induced inflammation and DNA damage in colonic epithelial cells. Cells. 2020; 9(9): 1980.

[106] Prickaerts P, Adriaens ME, Beucken TVD, et al. Hypoxia increases genome-wide bivalent epigenetic marking by specific gain of H3K27me3. Epigenetics Chromatin. 2016; 9: 46.

[107] Udayasuryan B, Zhou Z, Ahmad RN, et al. Fusobacterium nucleatum infection modulates the transcriptome and epigenome of HCT116 colorectal cancer cells in an oxygen-dependent manner. Commun Biol. 2024; 7(1): 551.

[108] Ganguli G, Mukherjee U, Sonawane A. Peroxisomes and oxidative stress: their implications in the modulation of cellular immunity during mycobacterial infection. Front Microbiol. 2019; 10: 1121.

[109] Sobhani I, Bergsten E, Couffin S, et al. Colorectal cancer-associated microbiota contributes to oncogenic epigenetic signatures. Proc Natl Acad Sci USA. 2019; 116(48): 24285-24295.

[110] Zhang S, Yang Y, Weng W, et al. Fusobacterium nucleatum promotes chemoresistance to 5-fluorouracil by upregulation of BIRC3 expression in colorectal cancer. J Exp Clin Cancer Res. 2019; 38(1): 14.

[111] Lu Q, Ding H, Li W. Role of Toll-like receptors in microbiota-associated gastrointestinal cancer metastasis. J Cancer Res Ther. 2013; 9: S142-9.

[112] Rajput S, Volk-Draper L, Ran S. TLR4 is a novel determinant of the response to paclitaxel in breast cancer. Mol Cancer Ther. 2013; 12(8): 1676-1687.

[113] Volk-Draper L, Hall K, Griggs C, et al. Paclitaxel therapy promotes breast cancer metastasis in a TLR4-dependent manner. Cancer Res. 2014; 74(19): 5421-5434.

[114] Yang H, Wang B, Wang T, et al. Toll-like receptor 4 prompts human breast cancer cells invasiveness via lipopolysaccharide stimulation and is overexpressed in patients with lymph node metastasis. PLoS One. 2014; 9(10):e109980.

[115] Grivennikov S. Inflammation and colorectal cancer: colitis-associated neoplasia. Semin Immunopathol. 2013; 35(2): 229-244.

[116] Grivennikov S, Greten F, Karin M. Immunity, inflammation, and cancer. Cell. 2010; 140(6): 883-899.

[117] Salvucci M, Crawford N, Stott K, Bullman S, Longley DB, Prehn JHM. Patients with mesenchymal tumours and high Fusobacteriales prevalence have worse prognosis in colorectal cancer (CRC). Gut. 2022; 71(8): 1600-1612.

[118] Bui FQ, Johnson L, Roberts J, et al. Fusobacterium nucleatum infection of gingival epithelial cells leads to NLRP3 inflammasome-dependent secretion of IL-1beta and the danger signals ASC and HMGB1. Cell Microbiol. 2016; 18(7): 970-981.

[119] Chen T, Li Q, Wu J, et al. Fusobacterium nucleatum promotes M2 polarization of macrophages in the microenvironment of colorectal tumours via a TLR4-dependent mechanism. Cancer Immunol Immunother. 2018; 67(10): 1635-1646.

[120] Hung S, Huang P, Almeida-da-Silva CLC, Atanasova KR, Yilmaz O, Ojcius DM. NLRX1 modulates differentially NLRP3 inflammasome activation and NF-kappaB signaling during Fusobacterium nucleatum infection. Microbes Infect. 2018; 20(9-10): 615-625.

[121] Nomoto D, Baba Y, Liu Y, et al. Fusobacterium nucleatum promotes esophageal squamous cell carcinoma progression via the NOD1/RIPK2/NF-kappaB pathway. Cancer Lett. 2022; 530: 59-67.

[122] Taniguchi K, Karin M. NF-kappaB, inflammation, immunity and cancer: coming of age. Nat Rev Immunol. 2018; 18(5): 309-324.

[123] Liu T, Zhang L, Joo D, Sun S. NF-kappaB signaling in inflammation. Signal Transduct Target Ther. 2017; 2:17023.

[124] Despins CA, Brown SD, Robinson AV, Mungall AJ, Allen-Vercoe E, Holt RA. Modulation of the host cell transcriptome and epigenome by Fusobacterium nucleatum. mBio. 2021; 12(5):e0206221.

[125] Proença MA, Biselli JM, Succi M, et al. Relationship between Fusobacterium nucleatum, inflammatory mediators and microRNAs in colorectal carcinogenesis. World J Gastroenterol. 2018; 24(47): 5351-5365.

[126] Shibayama O, Yoshiuchi K, Inagaki M, et al. Association between adjuvant regional radiotherapy and cognitive function in breast cancer patients treated with conservation therapy. Cancer Med. 2014; 3(3): 702-709.

[127] Dethlefsen C, Højfeldt G, Hojman P. The role of intratumoral and systemic IL-6 in breast cancer. Breast Cancer Res Treat. 2013; 138(3): 657-664.

[128] Fontanini G, Campani D, Roncella M, et al. Expression of interleukin 6 (IL-6) correlates with oestrogen receptor in human breast carcinoma. Br J Cancer. 1999; 80(3-4): 579-584.

[129] Korkaya H, Kim G, Davis A, et al. Activation of an IL6 inflammatory loop mediates trastuzumab resistance in HER2+ breast cancer by expanding the cancer stem cell population. Mol Cell. 2012; 47(4): 570-584.

[130] Madden K, Szpunar M, Brown E. beta-Adrenergic receptors (beta-AR) regulate VEGF and IL-6 production by divergent pathways in high beta-AR-expressing breast cancer cell lines. Breast Cancer Res Treat. 2011; 130(3): 747-758.

[131] Toussi D, Liu X, Massari P. The FomA porin from Fusobacterium nucleatum is a Toll-like receptor 2 agonist with immune adjuvant activity. Clin Vaccine Immunol. 2012; 19(7): 1093-1101.

[132] Wang Q, Yu C, Yue C, Liu X. Fusobacterium nucleatum produces cancer stem cell characteristics via EMT-resembling variations. Int J Clin Exp Pathol. 2020; 13(7): 1819-1828.

[133] Kozlowski L, Zakrzewska I, Tokajuk P, Wojtukiewicz MZ. Concentration of interleukin-6 (IL-6), interleukin-8 (IL-8) and interleukin-10 (IL-10) in blood serum of breast cancer patients. Rocz Akad Med Bialymst. 2003; 48: 82-84.

[134] Ma Y, Ren Y, Dai Z, Wu C, Ji Y, Xu J. IL-6, IL-8 and TNF-alpha levels correlate with disease stage in breast cancer patients. Adv Clin Exp Med. 2017; 26(3): 421-426.

[135] Engevik MA, Danhof HA, Ruan W, et al. Fusobacterium nucleatum secretes outer membrane vesicles and promotes intestinal inflammation. mBio. 2021; 12(2): e02706-20.

[136] Martin-Gallausiaux C, Malabirade A, Habier J, Wilmes P. Fusobacterium nucleatum extracellular vesicles modulate gut epithelial cell innate immunity via FomA and TLR2. Front Immunol. 2020; 11:583644.

[137] Kang W, Jia Z, Tang D, et al. Fusobacterium nucleatum facilitates apoptosis, ROS generation, and inflammatory cytokine production by activating AKT/MAPK and NF-kappaB signaling pathways in human gingival fibroblasts. Oxid Med Cell Longev. 2019; 2019:1681972.

[138] Zhao T, Wang X, Fu L, Yang K. Fusobacterium nucleatum: a new player in regulation of cancer development and therapeutic response. Cancer Drug Resist. 2022; 5(2): 436-450.

[139] Wang Q, Zhao L, Xu C, Zhou J, Wu Y. Fusobacterium nucleatum stimulates monocyte adhesion to and transmigration through endothelial cells. Arch Oral Biol. 2019; 100: 86-92.

[140] Si H, Yang Q, Hu H, Ding C, Wang H, Lin X. Colorectal cancer occurrence and treatment based on changes in intestinal flora. Semin Cancer Biol. 2021; 70: 3-10.

[141] Bashir A, Miskeen AY, Hazari YM, Asrafuzzaman S, Fazili KM. Fusobacterium nucleatum, inflammation, and immunity: the fire within human gut. Tumour Biol. 2016; 37(3): 2805-2810.

[142] Monu N, Frey A. Myeloid-derived suppressor cells and anti-tumor T cells: a complex relationship. Immunol Invest. 2012; 41(6-7): 595-613.

[143] Srivastava MK, Sinha P, Clements VK, Rodriguez P, Ostrand-Rosenberg S. Myeloid-derived suppressor cells inhibit T-cell activation by depleting cystine and cysteine. Cancer Res. 2010; 70(1): 68-77.

[144] Casey SC, Tong L, Li Y, et al. MYC regulates the antitumor immune response through CD47 and PD-L1. Science. 2016; 352(6282): 227-231.

[145] Juric V, O'Sullivan C, Stefanutti E, et al. MMP-9 inhibition promotes anti-tumor immunity through disruption of biochemical and physical barriers to T-cell trafficking to tumors. PLoS One. 2018; 13(11):e0207255.

[146] Huang H. Matrix metalloproteinase-9 (MMP-9) as a cancer biomarker and MMP-9 biosensors: recent advances. Sensors (Basel). 2018; 18(10): 3249.

[147] Shenker B, DiRienzo J. Suppression of human peripheral blood lymphocytes by Fusobacterium nucleatum. J Immunol. 1984; 132(5): 2357-2362.

[148] Jewett A, Hume WR, Le H, et al. Induction of apoptotic cell death in peripheral blood mononuclear and polymorphonuclear cells by an oral bacterium, Fusobacterium nucleatum. Infect Immun. 2000; 68(4): 1893-1898.

[149] Shenker B, Datar S. Fusobacterium nucleatum inhibits human T-cell activation by arresting cells in the mid-G1 phase of the cell cycle. Infect Immun. 1995; 63(12): 4830-4836.

[150] Kaplan CW, Ma X, Paranjpe A, et al. Fusobacterium nucleatum outer membrane proteins Fap2 and RadD induce cell death in human lymphocytes. Infect Immun. 2010; 78(11): 4773-4778.

[151] Mima K, Sukawa Y, Nishihara R, et al. Fusobacterium nucleatum and T cells in colorectal carcinoma. JAMA Oncol. 2015; 1(5): 653-661.

[152] Chen T, Li Q, Zhang X, et al. TOX expression decreases with progression of colorectal cancers and is associated with CD4 T-cell density and Fusobacterium nucleatum infection. Hum Pathol. 2018; 79: 93-101.

[153] Gur C, Ibrahim Y, Isaacson B, et al. Binding of the Fap2 protein of Fusobacterium nucleatum to human inhibitory receptor TIGIT protects tumors from immune cell attack. Immunity. 2015; 42(2): 344-355.

[154] Gur C, Maalouf N, Shhadeh A, et al. Fusobacterium nucleatum supresses anti-tumor immunity by activating CEACAM1. Oncoimmunology. 2019; 8(6):e1581531.

[155] Galaski J, Shhadeh A, Umaña A, et al. Fusobacterium nucleatum CbpF mediates inhibition of T cell function through CEACAM1 activation. Front Cell Infect Microbiol. 2021; 11:692544.

[156] Neuzillet C, Marchais M, Vacher S, et al. Prognostic value of intratumoral Fusobacterium nucleatum and association with immune-related gene expression in oral squamous cell carcinoma patients. Sci Rep. 2021; 11(1): 7870.

[157] Wang X, Liu Y, Lu Y, et al. Clinical impact of Fn-induced high expression of KIR2DL1 in CD8 T lymphocytes in oesophageal squamous cell carcinoma. Ann Med. 2022; 54(1): 51-62.

[158] Zhang N, Liu Y, Yang H, et al. Clinical significance of Fusobacterium nucleatum infection and regulatory T cell enrichment in esophageal squamous cell carcinoma. Pathol Oncol Res. 2021; 27:1609846.

[159] Jia Y, Wang K, Zhang Z, et al. TLR2/TLR4 activation induces Tregs and suppresses intestinal inflammation caused by Fusobacterium nucleatum in vivo. PLoS One. 2017; 12(10):e0186179.

[160] Kim YJ, Kim BK, Park SJ, Kim JH. Impact of Fusobacterium nucleatum in the gastrointestinal tract on natural killer cells. World J Gastroenterol. 2021; 27(29): 4879-4889.

[161] Park HE, Kim JH, Cho N, Lee HS, Kang GH. Intratumoral Fusobacterium nucleatum abundance correlates with macrophage infiltration and CDKN2A methylation in microsatellite-unstable colorectal carcinoma. Virchows Arch. 2017; 471(3): 329-336.

[162] Xu C, Fan L, Lin Y, et al. Fusobacterium nucleatum promotes colorectal cancer metastasis through miR-1322/CCL20 axis and M2 polarization. Gut Microbes. 2021; 13(1):1980347.

[163] Hu L, Liu Y, Kong X, et al. Fusobacterium nucleatum facilitates M2 macrophage polarization and colorectal carcinoma progression by activating TLR4/NF-kappaB/S100A9 cascade. Front Immunol. 2021; 12:658681.

[164] Wu J, Li K, Peng W, et al. Autoinducer-2 of Fusobacterium nucleatum promotes macrophage M1 polarization via TNFSF9/IL-1beta signaling. Int Immunopharmacol. 2019; 74:105724.

[165] Stanietsky N, Simic H, Arapovic J, et al. The interaction of TIGIT with PVR and PVRL2 inhibits human NK cell cytotoxicity. Proc Natl Acad Sci USA. 2009; 106(42): 17858-17863.

[166] Gray-Owen S, Blumberg R. CEACAM1: contact-dependent control of immunity. Nat Rev Immunol. 2006; 6(6): 433-446.

[167] Nie F, Zhang J, Tian H, et al. The role of CXCL2-mediated crosstalk between tumor cells and macrophages in Fusobacterium nucleatum-promoted oral squamous cell carcinoma progression. Cell Death Dis. 2024; 15(4): 277.

[168] Li W, Zhang Z, Wu R, et al. Fusobacterium nucleatum-derived outer membrane vesicles promote immunotherapy resistance via changes in tryptophan metabolism in tumour-associated macrophages. J Extracell Vesicles. 2025; 14(4):e70070.

[169] Quintero-Fabián S, Arreola R, Becerril-Villanueva E, et al. Role of matrix metalloproteinases in angiogenesis and cancer. Front Oncol. 2019; 9: 1370.

[170] Fujiwara N, Kitamura N, Yoshida K, Yamamoto T, Ozaki K, Kudo Y. Involvement of Fusobacterium species in oral cancer progression: a literature review including other types of cancer. Int J Mol Sci. 2020; 21(17): 6207.

[171] Zhang S, Li C, Liu J, et al. Fusobacterium nucleatum promotes epithelial-mesenchymal transiton through regulation of the lncRNA MIR4435-2HG/miR-296-5p/Akt2/SNAI1 signaling pathway. FEBS J. 2020; 287(18): 4032-4047.

[172] Yang Y, Jobin C. Far reach of Fusobacterium nucleatum in cancer metastasis. Gut. 2021; 70(8): 1427-1429.

[173] Guo S, Chen J, Chen F, Zeng Q, Liu WL, Zhang G. Exosomes derived from Fusobacterium nucleatum-infected colorectal cancer cells facilitate tumour metastasis by selectively carrying miR-1246/92b-3p/27a-3p and CXCL16. Gut. 2021; 70(8): 1507-1519.

[174] Ellis T, Kuehn M. Virulence and immunomodulatory roles of bacterial outer membrane vesicles. Microbiol Mol Biol Rev. 2010; 74(1): 81-94.

[175] Lin L, Shi Y, Choong C, Tai C. The fruits of Paris polyphylla inhibit colorectal cancer cell migration induced by Fusobacterium nucleatum-derived extracellular vesicles. Molecules. 2021; 26(13): 4081.

[176] Zhang X, Wang Y, Fan R, et al. Quantitative proteomic analysis of outer membrane vesicles from Fusobacterium nucleatum cultivated in the mimic cancer environment. Microbiol Spectr. 2023; 11(4):e0039423.

[177] Hong M, Li Z, Liu H, et al. Fusobacterium nucleatum aggravates rheumatoid arthritis through FadA-containing outer membrane vesicles. Cell Host Microbe. 2023; 31(5): 798-810 e7.

[178] Wang S, Song A, Xie J, et al. Fn-OMV potentiates ZBP1-mediated PANoptosis triggered by oncolytic HSV-1 to fuel antitumor immunity. Nat Commun. 2024; 15(1): 3669.

[179] Zhang L, Zhang D, Liu C, et al. Outer membrane vesicles derived from Fusobacterium nucleatum trigger periodontitis through host overimmunity. Adv Sci (Weinh). 2024; 11(47):e2400882.

[180] Mendes RT, Nguyen D, Stephens D, et al. Endothelial cell response to Fusobacterium nucleatum. Infect Immun. 2016; 84(7): 2141-2148.

[181] Yu M, Kim H, Park H. Fusobacterium nucleatum accelerates the progression of colitis-associated colorectal cancer by promoting EMT. Cancers (Basel). 2020; 12(10): 2728.

[182] Harrandah AM, Chukkapalli SS, Bhattacharyya I, Progulske-Fox A, Chan EKL. Fusobacteria modulate oral carcinogenesis and promote cancer progression. J Oral Microbiol. 2020; 13(1):1849493.

[183] yan X, liu L, li H, qin H, sun Z. Clinical significance of Fusobacterium nucleatum, epithelial-mesenchymal transition, and cancer stem cell markers in stage III/IV colorectal cancer patients. Onco Targets Ther. 2017; 10: 5031-5046.

[184] Allison SE, Chen Y, Petrovic N, et al. Activation of ALDH1A1 in MDA-MB-468 breast cancer cells that over-express CYP2J2 protects against paclitaxel-dependent cell death mediated by reactive oxygen species. Biochem Pharmacol. 2017; 143: 79-89.

[185] Karkhanis A, Hong Y, Chan E. Inhibition and inactivation of human CYP2J2: implications in cardiac pathophysiology and opportunities in cancer therapy. Biochem Pharmacol. 2017; 135: 12-21.

[186] Chu S, Cheng Z, Yin Z, et al. Airway Fusobacterium is associated with poor response to immunotherapy in lung cancer. Onco Targets Ther. 2022; 15: 201-213.

[187] Serna G, Ruiz-Pace F, Hernando J, et al. Fusobacterium nucleatum persistence and risk of recurrence after preoperative treatment in locally advanced rectal cancer. Ann Oncol. 2020; 31(10): 1366-1375.

[188] Gao Y, Bi D, Xie R, et al. Fusobacterium nucleatum enhances the efficacy of PD-L1 blockade in colorectal cancer. Signal Transduct Target Ther. 2021; 6(1): 398.

[189] Ding T, Chen Q, Liu H, et al. Single-cell RNA sequencing analysis reveals the distinct features of colorectal cancer with or without Fusobacterium nucleatum infection in PD-L1 blockade therapy. Heliyon. 2024; 10(18):e37511.

[190] Yang Y, Wang L, Peugnet-González I, Parada-Venegas D, Dijkstra G, Faber KN. cGAS-STING signaling pathway in intestinal homeostasis and diseases. Front Immunol. 2023; 14:1239142.

[191] Tong Y, Lu G, Wang Z, Hao S, Zhang G, Sun H. Correction: tubeimuside I improves the efficacy of a therapeutic Fusobacterium nucleatum dendritic cell-based vaccine against colorectal cancer. Front Immunol. 2025; 16:1639717.

[192] Chen L, Kang Z, Shen J, et al. An emerging antibacterial nanovaccine for enhanced chemotherapy by selectively eliminating tumor-colonizing bacteria. Sci Bull (Beijing). 2024; 69(16): 2565-2579.

[193] Kabwe M, Brown TL, Dashper S, et al. Genomic, morphological and functional characterisation of novel bacteriophage FNU1 capable of disrupting Fusobacterium nucleatum biofilms. Sci Rep. 2019; 9(1): 9107.

[194] Kowsarkhizi AS, Yousefi B, Rahimi A, Aliramezani A. Targeting Fusobacterium nucleatum in colorectal cancer: therapeutic strategies and future directions. Infect Agent Cancer. 2025; 20(1): 70.

[195] Binte Mohamed Yakob Adil SS, Kabwe M, Cianciarulo C, Nguyen TH, Irving H, Tucci J. IRAK3 knockout and wildtype THP-1 monocytes as models for endotoxin detection assays and fusobacterium nucleatum bacteriophage FNU1 cytokine induction. Int J Mol Sci. 2023; 24(20):15108.

[196] Kabwe M, Ayelign B, Afshar-Sterle S, Buchert M, Tucci J. Bacteriophage FNU1 negates Fusobacterium nucleatum induced cell growth, migration and chemotherapy resistance in gastrointestinal cancer cells. Front Cell Infect Microbiol. 2025; 15:1721411.

[197] Lam HYP, Lai M, Wang P, et al. A novel bacteriophage with the potential to inhibit Fusobacterium nucleatum-induced proliferation of colorectal cancer cells. Antibiotics (Basel). 2025; 14(1): 45.

[198] Könönen E, Kanervo A, Salminen K, Jousimies-Somer H. beta-lactamase production and antimicrobial susceptibility of oral heterogeneous Fusobacterium nucleatum populations in young children. Antimicrob Agents Chemother. 1999; 43(5): 1270-1273.

[199] Kim M, Yun SY, Lee Y, Lee H, Yong D, Lee K. Clinical differences in patients infected with Fusobacterium and antimicrobial susceptibility of fusobacterium isolates recovered at a tertiary-care hospital in Korea. Ann Lab Med. 2022; 42(2): 188-195.

[200] Kulis E, Cvitkovic I, Pavlovic N, Kumric M, Rusic D, Bozic J. A comprehensive review of antibiotic resistance in the oral microbiota: mechanisms, drivers, and emerging therapeutic strategies. Antibiotics (Basel). 2025; 14(8): 828.

[201] Boattini M, Bianco G, Bastos P, et al. Diagnostic and epidemiological landscape of anaerobic bacteria in Europe, 2020–2023 (ANAEuROBE). Int J Antimicrob Agents. 2025; 65(6):107478.

[202] Hamada T, Nowak JA, Milner DA, Song M, Ogino S. Integration of microbiology, molecular pathology, and epidemiology: a new paradigm to explore the pathogenesis of microbiome-driven neoplasms. J Pathol. 2019; 247(5): 615-628.

[203] Inamura K, Hamada T, Bullman S, Ugai T, Yachida S, Ogino S. Cancer as microenvironmental, systemic and environmental diseases: opportunity for transdisciplinary microbiomics science. Gut. 2022; 71(10): 2107-2122.

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