Potential Mechanisms Underlying Ferroptosis-Associated NK Cell Dysfunction and Its Regulatory Networks in the Tumor Microenvironment

Abstract

Ferroptosis is a regulated form of cell death characterized by iron-dependent lipid peroxidation. Its role in tumor immunity has attracted increasing attention in recent years. Natural killer (NK) cells are important antitumor immune effector cells, whereas metabolic reprogramming and oxidative stress in the tumor microenvironment (TME) may promote their functional exhaustion and ferroptotic cell death. This review summarizes the potential effects of cancer-associated fibroblasts (CAFs), the kynurenine metabolic pathway, and the tumor microenvironment itself on NK cell ferroptosis. Existing studies suggest that CAFs-induced NK cell ferroptosis can occur through dysregulated iron metabolism and ferritinophagy. In addition, the accumulation of kynurenine may further promote iron-dependent lipid peroxidation in NK cells. The amino acid transporter SLC7A5 may participate in this process by mediating kynurenine uptake, although direct evidence remains limited. Moreover, nutrient deprivation, lipid metabolic reprogramming, and redox imbalance in the TME may collectively increase the susceptibility of NK cells to ferroptosis. Ferroptosis of NK cells may be an important mechanism connecting tumor metabolic reprogramming and immune dysfunction, and is expected to become a new direction for immunotherapy intervention.