Immunotherapy in triple-negative breast cancer: From molecular mechanisms to precision medicine-overcoming resistance and optimizing clinical outcomes

Abstract

Triple-negative breast cancer (TNBC) is the most violent type of breast cancer, in which estrogen receptors (ER), progesterone receptors (PR), and human epidermal growth factor receptor 2 (HER2) are not expressed, and with which has a disproportionately high poor survival rate. Recent developments in immuno-oncology have radically changed the treatment of TNBC based on its characteristic immunogenic pathophysiology such as high genomic instability, high tumour mutational burden (TMB), homologous recombination deficiency (HRD), and high tumour-infiltrating lymphocytes (TILs). Chemo-immunotherapy with pembrolizumab has become the first to show the ultimate overall survival advantage in the early-stage TNBC (KEYNOTE-522) with 65 % pathologic complete response (pCR) and 86.6 % 5-year survival, establishing a novel standard-of-care. Nevertheless, intrinsic or acquired resistance to immune checkpoint blockade (ICB) by tumour-intrinsic signalling (Wnt/β-catenin, PI3K/AKT/mTOR activation, loss of antigen-presentation) and suppressive tumour microenvironmental interactions between myeloid-derived suppressor cells (MDSCs), regulatory T cells (Tregs), and desmoplastic cancer-associated fibroblasts (CAFs) occur in 40-50 % of patients. Mechanistically rational precision medicine strategies to these barriers are currently in rapid development, such as synergistic combinations of poly (ADP-ribose) polymerase (PARP) inhibitors and checkpoint blockades, dual-checkpoint therapy (PD-1/CTLA-4; PD-1/LAG-3), CD40-based myeloid reprogramming and metabolic checkpoint inhibitor targeting lactate transport and glycolysis. Immunomodulatory delivery systems based on nanotechnology, artificial-intelligence-directed biomarker stratification, have become the next-generation systems to optimize treatment personalization, allow real-time resistance prediction, and extend durable immune control. Also, the neoantigen-mRNA vaccines and gut microbiome modulation are broadening the clinical perspective to build enduring immunologic memory and negate metastatic relapse. Mechanistic insights alongside multi-omics, computational, and biologic innovation are making a paradigm shift in TNBC- once historically fatal, a disease that could be controlled and cured. Further development of the predictive biomarkers, equity of access plans and avoidance of immune toxicity will be central to universal implementation of these immunotherapy advances.

Keywords: Cancer immunotherapy; Immune Resistance; Immune checkpoint inhibition; Neoantigen Vaccines; Triple-negative breast cancer (TNBC); Tumor microenvironment; Tumor-Infiltrating Lymphocytes (TILs); precision oncology.