Intratumoral microbiome in breast cancer: A hidden player in tumor development, progression and treatment response

The intratumoral microbiome has recently emerged as a critical component of the tumor microenvironment in breast cancer (BC). BC exhibits a uniquely rich and diverse microbial community, characterized by phyla such as Proteobacteria, Firmicutes, Actinobacteria, and Bacteroidetes. In addition, distinct microbial signatures were observed in different molecular subtypes, with hormone receptor-positive BC showing the highest microbial diversity and the most robust microbiome. These microbial constituents interact with neoplastic and immune cells, influencing estrogen metabolism, DNA damage, epithelial-to-mesenchymal transition (EMT), inflammation, and response to anticancer therapy. For instance, Fusobacterium nucleatum is among the main microbial components implicated in BC, contributing to carcinogenesis, tumor growth, and metastasis through mechanisms involving DNA damage (e.g., activating the E-cadherin/(3-catenin signaling pathway), EMT (e.g., inducing the expression of EMT markers, including cadherins and vimentin), and immunoregulatory effects (e.g., regulating IL-1(3 expression and activating the TLR4/NF-kappa B signaling pathway). It has also been shown to induce chemoresistance by enhancing cancer cell stemness and viability, whereas its elimination improves sensitivity to anticancer therapies and immunotherapy. Besides investigating the specific activity of microbial components, recent studies have focused on the intratumoral microbiome prognostic role. Methodological variability remains a significant barrier to standardization and cross-study comparisons. Nevertheless, subtype-specific microbial signatures have demonstrated prognostic and predictive value, correlating with stage, treatment response, and immune cell infiltration. Understanding the interplay between the intratumoral microbiome, host genetics, and treatment response may ultimately inform the development of microbiome-based biomarkers and therapeutic strategies, positioning the tumor microbiota as a potential modifiable target in personalized BC care.