Reprogramming natural killer cells in the tumor microenvironment: Challenges and therapeutic opportunities

Natural killer (NK) cells are central effectors of innate immunity, traditionally viewed as rapid responders capable of recognizing and eliminating malignant or virus-infected cells without prior sensitization. Their combined capacity to mediate direct cytotoxicity and secret cytokines has established NK cells as attractive and powerful effectors in immunotherapeutic strategies, including CAR-NK cell therapies and cytokine-based stimulation. However, recent discoveries challenge the notion of NK cells as uniformly antitumor. In certain tumor microenvironments (TME), NK cells undergo functional reprogramming into regulatory or dysfunctional phenotypes that can suppress CD8⁺ T cell activities and contribute to resistance against immune checkpoint blockade (ICB). These suppressive tumor-associated NK cells (TANKs) may limit antitumor immunity through cytokine competition, immune editing, and modulation of dendritic cell (DC) function. This review critically examines the dual roles of NK cells in cancer immunity, highlighting both their cytotoxic potential and their emerging immunoregulatory functions. We discuss how cytokine signaling, spatial distribution, and tumor-induced plasticity shape NK cell behavior, and evaluate the therapeutic implications of these findings. By addressing a critical knowledge gap in NK cell biology and integrating mechanistic insights with clinical perspectives, this review provides a framework for leveraging or reprogramming NK cells to enhance cancer immunotherapy outcomes.