Immunotherapy innovations in triple-negative breast cancer: targeting checkpoints, combinations, and biomarkers

Triple-negative breast cancer (TNBC), an aggressive subtype lacking estrogen receptor (ER), progesterone receptor (PR), and HER2 expression, accounts for 10-20% of breast cancers and is characterized by high metastatic potential and poor survival outcomes. Despite advancements in chemotherapy, the 5-year survival rate for metastatic TNBC remains below 30%, underscoring the need for innovative therapeutic approaches. This review comprehensively examines recent breakthroughs in TNBC immunotherapy, focusing on immune checkpoint inhibitors (ICIs), combination strategies, and biomarker-driven therapy. Landmark trials such as KEYNOTE-355 and IMpassion130 have demonstrated that combining PD-1/PD-L1 inhibitors with chemotherapy improves survival in PD-L1-positive metastatic TNBC. Beyond monotherapy, combination therapies-including dual checkpoint inhibition, PARP inhibitors in BRCA-mutated tumors, and antibody-drug conjugates (ADCs) -show promise in overcoming resistance and enhancing antitumor immunity. Emerging targets further expand therapeutic possibilities, though their paradoxical roles as biomarkers and immunosuppressive mediators require precision-based approaches. Biomarkers like PD-L1, tumor-infiltrating lymphocytes (TILs), tumor mutational burden (TMB), and circulating tumor DNA (ctDNA) are critical for patient stratification and predicting immunotherapy response. Despite progress, challenges persist, including tumor heterogeneity, resistance mechanisms, and access to advanced therapies. Future directions emphasize next-generation ICIs, optimized combination regimens, and AI-driven biomarker integration to achieve durable, personalized treatments. This review underscores the potential of immunotherapy to redefine TNBC management while highlighting the imperative for continued innovation to address unmet clinical needs.