Integrative analysis identifies SPP1 and ECM remodeling as candidate features associated with bisphenol a exposure and an immunosuppressive microenvironment in triple-negative breast cancer

Bisphenol A (BPA) is a prevalent endocrine-disrupting chemical linked to breast cancer risk, but whether it contributes specifically to the immunosuppressive phenotype of triple-negative breast cancer (TNBC) remains largely unexplored. This hypothesis-generating study aimed to identify candidate molecular targets and pathways that may link BPA exposure to TNBC progression, focusing on the immune microenvironment. We integrated network toxicology, molecular docking, and spatial transcriptomics. Differentially expressed genes (DEGs) from hyperplastic breast tissues (GSE16873) were intersected with high-confidence BPA-associated genes. Core hub genes were identified via protein-protein interaction (PPI) network topology, and their clinical relevance was explored in TNBC cohorts. Molecular docking simulated potential BPA–target interactions. Spatial transcriptomics was used to characterize the spatial distribution of top candidates. Seventeen overlapping genes were identified. SPP1 emerged as a top-ranked hub gene. High SPP1 expression was associated with poorer survival in the basal-like subtype (as a surrogate for TNBC) and correlated with an immunosuppressive microenvironment (macrophage enrichment, lower CD8⁺T-cell abundance). Molecular docking predicted a potential BPA–SPP1 interaction (ΔG = − 6.4 kcal/mol). Spatial transcriptomics revealed pervasive SPP1 enrichment in tumor regions, colocalizing with CD68⁺macrophages and showing limited overlap with CD8A⁺T-cells. In a separate SPP1-low TNBC sample, high-resolution mapping identified ECM-enriched hotspots (e.g., COL3A1, COL1A1) that spatially correlated with macrophage-rich areas. Multivariable Cox regression further demonstrated that SPP1’s prognostic effect was largely mediated by the immune microenvironment. This integrative analysis generates the hypothesis that SPP1 and ECM remodeling may represent candidate features linking BPA exposure to an immunosuppressive microenvironment in TNBC. The proposed BPA–ECM–SPP1 axis warrants future functional validation.