Immunotherapy in triple-negative breast cancer: mechanisms of resistance and emerging approaches: a narrative review

Triple-negative breast cancer (TNBC) is characterized by less treatment responsiveness and poorer prognosis than other breast cancer subtypes. The introduction of anti-programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) immunotherapy has expanded the therapeutic options beyond conventional chemotherapy, leading to the adoption of pembrolizumab-based regimens in both adjuvant and first-line palliative settings. However, in contrast to other tumor types that respond robustly to immune checkpoint inhibitors, the efficacy of PD-1/PD-L1 blockade in TNBC remains modest. Multiple factors contribute to this limited response, including the heterogeneity of PD-L1 expression, presence of an immunosuppressive tumor microenvironment regulated by complex immunomodulatory pathways, differences in mutational burden and neoantigen presentation, quantity and functional exhaustion of tumor-infiltrating lymphocytes, and variable synergy with combination partners. Numerous combination strategies have been actively investigated to enhance immunotherapeutic efficacy. Among these, antibody drug conjugates (ADCs) have shown the most promising results. The phase III ASCENT-04/KEYNOTE-D19 trial demonstrated that the combination of sacituzumab govitecan and pembrolizumab significantly improved progression-free survival in patients with PD-L1-positive metastatic TNBC, establishing this regimen as a potential new first-line standard, pending guideline adoption. Although the overall survival data are still immature, the trend appears to be favorable. Other ADCs are being explored in early phase studies, and targeted therapies such as poly(ADP-ribose) polymerase and protein kinase B inhibitors have also shown preliminary activity in smaller trials. Further refinement of these strategies through biomarker-driven, large-scale studies is warranted to identify the most effective combinations and to improve outcomes in patients with TNBC.