Exploring the Microbiome in Breast Cancer: The Role of Fusobacterium nucleatum as an Onco-Immune Modulator

Abstract

The breast microbiome remains stable throughout a woman's life. The breast is not a sterile organ, and its microbiota exhibits a distinct composition compared to other body sites. The breast microbiome is a community characterized by an abundance of Proteobacteria and Firmicutes, which represent the result of host microbial adaptation to the fatty acid environment in the tissue. The breast microbiome demonstrates dynamic adaptability during lactation, responding to maternal physiological changes and infant interactions. This microbial plasticity modulates local immune responses, maintains epithelial integrity, and supports tissue homeostasis, thereby influencing both breast health and milk composition. Disruptions in this balance, the dysbiosis, are closely linked to inflammatory breast conditions such as mastitis. Risk factors for breast cancer (BC) include genetic mutations, late menopause, obesity, estrogen metabolism, and alterations in gut microbial diversity. Gut microbiota can increase estrogen bioavailability by deconjugating estrogen-glucuronide moieties. Perturbations of this set of bacterial genes and metabolites, called the estrobolome, increases circulating estrogens and the risk of BC. Fusobacterium nucleatum has recently been associated with BC. It moves from the oral cavity to other body sites hematogenously. This review deals with the characteristics of the breast microbiome, with a focus on F. nucleatum, highlighting its dual role in promoting tumor growth and modulating immune responses. F. nucleatum acts both on the Wnt/β-catenin pathway by positively regulating MYC expression and on apoptosis by inhibiting caspase 8. Furthermore, F. nucleatum binds to TIGIT and CEACAM1, inhibiting T-cell cytotoxic activity and protecting tumor cells from immune cell attack. F. nucleatum also inhibits T-cell function through the recruitment of myeloid suppressor cells (MDSCs). These cells express PD-L1, which further reduces T-cell activation. A deeper understanding of F. nucleatum biology and its interactions with host cells and co-existing symbiotic microbiota could aid in the development of personalized anticancer therapy.

Keywords: FadA; Fap2; Fusobacterium nucleatum; MDSC; TIGIT; Wnt/β-catenin; breast cancer; breast milk; estrobolome; immune response; microbiome.

Figure 1

Healthy breast versus inflammatory condition. The breast microbiome in health is characterized by a balanced microbial community dominated by commensals such as Lactobacillus, Bifidobacterium, and Sphingomonas, supporting immune tolerance and neonatal gut colonization. In contrast, dysbiosis during inflammatory conditions such as mastitis or maternal obesity leads to an overgrowth of opportunistic pathogens (e.g., Staphylococcus aureus and E. coli), immune cell infiltration, and altered cytokine profiles. These changes can potentially disrupt lactation and compromise the long-term health of both infant and mothers [15]. Image created with BioRender (https://biorender.com; last accessed on 24 August 2025).

Figure 2

Retrograde inoculation of F. nucleatum into the lactating mammary gland. This schematic illustrates the retrograde inoculation route, whereby microbes from the infant’s oral cavity are transferred back into the mammary ducts during breastfeeding. This process occurs as negative pressure and peristaltic tongue movements during suckling allow milk and saliva to transiently flow back into the milk ducts. Microbial genera such as Streptococcus, Veillonella, Fusobacterium (species nucleatum), and Actinomyces have been identified as prominent oral-derived taxa colonizing breast milk via this mechanism [38,41]. This bidirectional exchange contributes to the shaping of both the milk microbiome and the infant gut microbiota, enhancing microbial diversity and potentially supporting immunological development. The figure also shows the changes in the microbiota of a cancerous breast environment. Image created with BioRender (https://biorender.com; last accessed on 18 July 2025).

Figure 3

F. nucleatum as an onco-immune modulator. The figure illustrates the dual role of F. nucleatum. Protein Fap2 of F. nucleatum binds to the cell adhesion molecule CEACAM1 and to immune receptor TIGIT, both expressed by T and NK cells, inhibiting the function of immune cells and causing cancer cells evasion. At the same time, the bacterium, through its adhesin FadA, binds to E-cadherin, activating the Wnt/β-catenin oncogenetic pathway and causing tumor proliferation and progression. Image created with BioRender (https://biorender.com; last accessed on 18 July 2025).