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Life sciences · Journal article
Clinical Proteomics · September 26, 2026
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Treatment options for the highly aggressive triple-negative breast cancer (TNBC) subtype remain limited, though the immune microenvironment represents a promising therapeutic target. We conducted a histology resolved tumor microenvironment analysis of TNBC by employing deep quantitative proteomic profiling of enriched tumor epithelium and the stromal microenvironment using high-resolution liquid chromatography tandem mass spectrometry (LC–MS/MS). Downstream analyses were then directed toward immune admixture signaling, guided by histopathologic assessment and quantitative proteome deconvolution-derived immune cell composition scores. Tumor epithelium and tumor-involved stromal microenvironment were laser microdissected from primary chemotherapy-naïve TNBC formalin-fixed paraffin-embedded tumors (n = 12 specimens obtained from 11 unique patients) to support quantitative proteomic analysis. Pathology-assigned immune classifications (n = 6 each of immune hot and immune cold specimens) were refined using ProteoMixture admixture deconvolution signatures. Proteomic alterations between immune hot versus cold tumor and stroma were independently examined and integrated with previously published breast cancer gene module (GM) signatures derived from previously published single-cell RNA-seq data from 26 breast cancers, including 10 TNBCs. Quantitative proteomics using data-independent acquisition identified 6,842 proteins co-quantified in all samples. Differential analyses revealed profound compartmentalization of TNBC immune signaling. Immune hot stroma exhibited robust innate and adaptive signatures, whereas immune hot tumor epithelium showed weaker, predominantly innate inflammatory signaling. Stromal profiles correlated with interferon, antigen presentation, and tumor plasticity modules, whereas epithelium showed heterogeneous metabolic and apoptotic signatures. Compartment- and immune-specific alterations in mTOR signaling were also identified. PI3K/AKT/mTORC1 signaling and downstream metabolic programs were largely enriched in immune hot stroma. Immune cold tumors were enriched for mitotic and cell cycle progression pathways. Pathway enrichment patterns suggest that immune sensing and infiltration predominantly localize to the TNBC stroma, while epithelial tumor cells exhibit innate inflammatory signaling that may be inadequate to surmount tumor-intrinsic immunosuppression or to robustly activate and/or engage adaptive immunity. These findings highlight the need for therapies targeting both stromal immune dysfunction and mechanisms of tumor resistance and further suggest that immune infiltration alone does not predict effective antitumor immunity in TNBC.