Abstract Background: Triple-negative breast cancer (TNBC) is a heterogeneous and aggressive subtype associated with poor prognosis and limited therapeutic options. Molecular and immunological characterization of the tumor microenvironment (TME) may support the identification of prognostic biomarkers and new therapeutic targets. Objective: To evaluate, through an in silico approach, the gene expression profile and immune composition of the TNBC tumor microenvironment compared to hormone receptor-positive (HR+) and HER2-positive subtypes. Methods: We used clinical and RNA-seq data from the TCGA-BRCA dataset, comprising 1,101 breast cancer patients. Tumor samples were classified into TNBC, HR+, and HER2+ groups. Immune and stromal cell composition was estimated using the CIBERSORT and ESTIMATE algorithms. Differentially expressed genes (DEGs) were identified using the DESeq2 package. Gene co-expression network analysis was conducted using WGCNA, and overall survival was analyzed using Kaplan–Meier curves. Results: A total of 226 DEGs were identified: 206 in the TNBC vs HR+ comparison and 96 in the TNBC vs HER2+ comparison, with 76 genes shared between both. TNBC samples showed higher levels of CD8+ T cells (p 0.01), activated dendritic cells, and immune scores (p 0.001), but also increased T regulatory cells (p 0.05) and M2 macrophages (p 0.0001), suggesting a complex immune landscape with both cytotoxic and immunosuppressive elements. WGCNA identified two relevant modules: the blue module, correlated with stromal score, included DSG1, ACAN, RHCG, and KRT6C, genes linked to extracellular matrix remodeling; and the turquoise module, correlated with immune score, included CD274 (PD-L1), LAG3, IDO1, CXCL10, and GZMB, markers of immune activation and evasion. Survival analysis showed that CXCL13, CD3G, and GZMB were significantly associated with worse overall survival (p 0.05). Conclusion: This integrative analysis revealed distinct gene signatures and immune patterns in TNBC, with enrichment of pathways related to inflammation, immunosuppression, and stromal remodeling. These findings suggest potential prognostic and predictive biomarkers and reinforce the TME as a relevant target for future therapeutic strategies. These results highlight promising targets for translational research and contribute to a better understanding of TNBC biological heterogeneity. Citation Format: D. L. Nunes, R. V. Gisele, V. D. Bertoni, C. A. Rocha. Transcriptomic Analysis of Differentially Expressed Genes in Triple-Negative Breast Cancer: Insights into Imune Cell Infiltration and the Tumor Microenvironment abstract. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS3-13-14.
Nunes et al. (2026) studied this question.