Multi-omics characterization of P2RX4-associated immune microenvironment features and proof-of-concept observations of peritumoral radiomic phenotypes in TNBC

Abstract Background Triple-negative breast cancer (TNBC) is characterized by a highly heterogeneous and immunosuppressive tumor microenvironment (TME). While the ATP-gated receptor P2RX4 is associated with inflammation, its cell-specific expression patterns, associations with TME features, and potential imaging correlates in TNBC remain incompletely characterized. This study aimed to characterize the cell-specific expression of P2RX4, its association with the tumor immune microenvironment, and its potential non-invasive imaging correlates in TNBC. Methods We integrated single-cell RNA sequencing from GEO and bulk transcriptomics from TCGA-BRCA, with cross-cohort validation using the METABRIC cohort. Additionally, we incorporated dynamic contrast-enhanced MRI data from TCIA to provide exploratory macroscopic observations of the 3-mm peritumoral habitat. Results scRNA-seq analysis showed that P2RX4 expression was predominantly enriched in epithelial/tumor cells in the analyzed TNBC samples. Across transcriptomic analyses, P2RX4 expression was positively associated with CD163 expression and hypoxia-related transcriptional features, with modest correlation magnitudes. P2RX4 and P2RX7 showed different correlation patterns with selected microenvironment-related markers. In the analyzed TNBC cohort, P2RX4 expression was negatively correlated with VIM and positively correlated with CDH1; these associations do not establish an effect on EMT or stromal remodeling. Exploratory survival analyses showed an association between high P2RX4 expression and favorable overall survival in the Pan-BRCA cohort but not in the TNBC subgroup; this association was sensitive to the data-driven expression cutpoint. Imaging observations in four matched MRI cases were descriptive and hypothesis-generating and do not establish an imaging–molecular association or validate an imaging biomarker. Conclusions In the analyzed TNBC datasets, P2RX4 expression was associated with CD163 expression and hypoxia-related transcriptional features. These molecular findings, together with descriptive peritumoral MRI observations in four cases, generate hypotheses for future studies of P2RX4-associated microenvironmental features and potential imaging correlates.