Next-Generation Therapeutic Targets in Triple-Negative Breast Cancer

Triple-negative breast cancer (TNBC) lacks estrogen and progesterone receptors, and estrogen receptor/progesterone receptor/human epidermal growth factor receptor 2 expression, and is associated with early relapse, visceral metastasis, and limited targeted options. High-throughput profiling supports TNBC as a collection of molecularly distinct diseases with exploitable vulnerabilities across DNA-damage response, cell-cycle control, receptor tyrosine kinase signaling, metabolism, and anti-tumor immunity. Clinically, immune checkpoint blockade has shifted standards of care in selected settings, and biomarker enrichment is increasingly central to trial design. In parallel, DNA repair-directed approaches, including poly(ADP-ribose) polymerase inhibitors in BRCA1/2-mutant and homologous recombination-deficient tumors, are being extended through rational combinations that intensify replication stress (e.g., ataxia telangiectasia and Rad3-related protein, WEE1, or checkpoint kinase 1 inhibition) to deepen responses and delay resistance. Additional candidate targets, including androgen receptor-driven disease biology, epidermal growth factor receptor, fibroblast growth factor receptor, vascular endothelial growth factor receptor signaling, and emerging antibody-drug conjugate antigens highlight the importance of matching therapy to subtype and tumor microenvironment context. Metabolic reprogramming (glycolysis, fatty-acid oxidation/synthesis, and amino-acid use) intersects with therapy resistance and may provide complementary combination opportunities. In this study, we synthesize recent advances in actionable TNBC pathways, summarize key preclinical and clinical evidence, and propose a pragmatic framework for biomarker-led combinations that integrate DNA repair, cell-cycle, metabolic, and immune vulnerabilities.