Integrating molecular targeting and immune modulation in triple-negative breast cancer: from mechanistic insights to therapeutic innovation

Triple-negative breast cancer (TNBC) remains a clinically aggressive subtype of breast cancer, defined by the absence of estrogen receptor, progesterone receptor, and HER2 amplification, and disproportionately affecting younger and racially diverse populations. Despite conventional chemotherapy, TNBC patients often face poor prognoses due to the lack of actionable molecular targets and early metastatic potential. Advances in molecular profiling have unveiled distinct TNBC subtypes and actionable vulnerabilities, including BRCA1/2 mutations and PI3K/AKT/mTOR dysregulation. Therapies targeting DNA repair pathways, angiogenesis, and androgen receptor signaling—particularly via PARP inhibitors and antibody–drug conjugates like sacituzumab govitecan—have demonstrated clinical benefit. Concurrently, TNBC’s immunogenic nature, reflected in dense tumor-infiltrating lymphocytes (TILs), has driven the integration of immune checkpoint inhibitors. However, both primary and acquired resistance remain major barriers. This review delineates recent developments in targeted and immunotherapeutic strategies, emphasizing the role of TILs in shaping treatment response and highlighting combinatorial approaches that synergize molecular targeting with immunomodulation. Through a comprehensive understanding of TNBC’s molecular and immune landscape, we propose new therapeutic trajectories to improve clinical outcomes in this challenging malignancy.