Modifying Epigenetic Landscapes to Restore Immune Therapeutic Responses in Triple Negative Breast Cancer

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer defined by the absence of estrogen and progesterone receptors, as well as the lack of human epidermal growth factor 2 receptor overexpression. TNBC is associated with early onset, high metastatic potential, therapeutic resistance, and poor clinical outcomes exacerbated by the limited availability of effective targeted therapies. Advances in multi-omics profiling have further stratified TNBC into distinct molecular subtypes, each exhibiting unique genomic, epigenomic, and immune-related features that influence therapeutic responsiveness. This review explores the interplay between TNBC molecular heterogeneity, immune evasion mechanisms, and epigenetic regulation. TNBC demonstrates variable immunogenicity, with tumor-infiltrating lymphocytes serving as important prognostic and predictive biomarkers. However, immune escape commonly occurs through tumor microenvironment remodeling, T-cell exhaustion, cancer stem cell enrichment, and immune checkpoint pathways activation. Although immune checkpoint inhibitors have improved outcomes in selected patients, particularly in combination with chemotherapy, primary and acquired therapeutic resistance remain a significant challenge. Emerging evidence highlights the central role of epigenetic mechanisms in regulating immune-related gene expression and shaping the tumor immune microenvironment. Epigenetic silencing of antigen presentation machinery, interferon signaling pathways, and chemokine expression contributes to immune evasion and immunotherapy resistance. Importantly, pharmacological modulation of epigenetic regulators can restore immune recognition and induce “viral mimicry” through reactivation of endogenous retroelements, thereby enhancing antitumor immunity. Collectively, this review underscores the therapeutic potential of integrating epigenetic therapies with immunotherapy and chemotherapy to overcome immune resistance in TNBC. A deeper understanding of epigenetic-immune interactions may facilitate the development of more precise and effective treatment strategies tailored to TNBC molecular subtypes.