Natural Killer Cells in Health and Disease: Mechanisms of Dysfunction and Emerging Therapeutic Targets

Natural Killer (NK) cells are a key component of the innate immune system, responsible for the rapid detection and elimination of virally infected and malignant cells. As our knowledge of immune cells including NK cells continues to expand, recent research revealed a complex network of intrinsic and extrinsic factors that modulate NK cell function in both health and disease. This review explores diverse pathological contexts in which NK cell activity is impaired, including severe viral infections (e.g., COVID-19), cancers such as multiple myeloma, immune evasion via checkpoint molecules like IGSF8, and the stage of immunosenescence due to aging. We also highlight metabolic exhaustion observed in Myalgic Encephalomyelitis / Chronic Fatigue Syndrome (ME/CFS) and novel epigenetic suppression mechanisms mediated by the SUPT16H–BRD4 axis. Transcriptional regulators T-BET and EOMES are shown to be indispensable for maintaining NK cell identity and cytotoxic integrity. Through these case studies, we identify shared patterns of dysfunction, such as impaired cytokine signaling, defective immune synapse formation, and energy metabolism failure, and discuss the emerging therapeutic strategies aimed at reversing them. A comprehensive list of molecular markers discussed across these cases is provided in Supplementary Table 1. Together, these findings emphasize the critical role of NK cells in immune surveillance and emphasize their potential as targets for innovative immunotherapies in infection, cancer, and chronic immune disorders.