Immune Checkpoint Blockade and Emerging Combination Platforms in Breast Cancer: A Narrative Review

Maryam Abbaspour,1 Nafiseh Esmaeil,2 Vajihe Akbari,1 Mohammad Ghoreishi,1 Haniyeh Rafiepoor3 1Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, Isfahan University of Medical Sciences, Isfahan, Iran; 2Department of Immunology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran; 3Cancer Biology Research Center, Cancer Institute, Tehran University of Medical Sciences, Tehran, IranCorrespondence: Nafiseh Esmaeil, Department of Immunology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, 81744-176, Iran, Tel +98 31 37929097, Fax +98 3113 7929031, Email [email protected]: This narrative review examines recent progress in immunotherapy for breast cancer (BC), focusing on immune checkpoint inhibitors (ICIs) alone and in combination with other modalities. Landmark trials such as KEYNOTE-522 and IMpassion130 have established the efficacy of pembrolizumab and atezolizumab in triple-negative breast cancer (TNBC). However, BC remains a leading cause of cancer-related fatalities, underscoring the need for novel approaches. We synthesize combination strategies into three mechanistic categories: (I) those that remodel the immunosuppressive tumor microenvironment (chemotherapy, PARP inhibitors, oncolytic viruses); (II) those that enhance effector cell persistence (CAR-T, CAR-NK, cytokine support); and (III) those that modulate immune checkpoint axes beyond PD-1/CTLA-4 (LAG-3, TIM-3, TIGIT). Combining ICIs with CAR-T cells, CAR-NK cells, oncolytic viruses, and exosomes has been shown to improve antitumor immune responses. This review provides a translational framework for biomarker-driven patient stratification and critically evaluates the clinical maturity of emerging platforms. Further research and clinical trials are needed to expand applicability across BC subtypes and improve patient outcomes.Keywords: breast cancer, immunotherapy, checkpoint inhibitors, CAR T cells, CAR NK cells, oncolytic viruses, exosomes