Outsmarting the Immune System: The Complexities of Breast Cancer Immune Evasion from NK cells Surveillance

Breast cancer (BC) remains one of the leading causes of cancer-related deaths among women worldwide, largely attributable to its heterogeneity and capacity to evade immune surveillance. Natural killer (NK) cells are essential effectors of the innate immune system, mediating early recognition and destruction of malignant cells. However, BC employs multiple strategies to escape NK cell–mediated cytotoxicity. These include downregulation of activating ligands, upregulation of inhibitory receptors, altered cytokine and chemokine signaling, and the immunosuppressive effects exerted by the tumor microenvironment through stromal components and soluble mediators. This review article assesses both the therapeutic potential and limitations of targeting these evasion pathways. Finally, we discuss future directions in NK cell–based immunotherapy, including personalized approaches, advanced delivery systems, and combinatorial strategies aimed at promoting NK-cell survival, tissue infiltration, and cytotoxic function against tumors. A clear understanding of these evasion mechanisms is key to designing more effective treatments such as CAR-NK cells, checkpoint inhibitors, and cytokine-based therapies to reactivate the functionality of NK cells and improve clinical outcomes in breast cancer. This narrative review summarizes relevant studies identified through a structured search up to mid-2025, focusing on NK-cell biology, immune evasion, and therapeutic applications in breast cancer.