Interplay between natural killer cells and ferroptosis: novel insights in tumor immunity and therapeutic potential

Natural killer (NK) cells are essential components of the innate immune system, executing antitumor functions through direct cytotoxicity and cytokine release. Increasing evidence highlights a bidirectional relationship between NK cell activity and ferroptosis, a regulated form of iron-dependent lipid peroxidation, within the tumor microenvironment (TME). NK cell-secreted interferon-gamma can inhibit tumor antioxidant defenses, such as SLC7A11, thereby sensitizing cancer cells to ferroptotic death. In turn, ferroptotic tumor cells release damage-associated molecular patterns that modulate NK cell recruitment and activation. The TME, characterized by hypoxia, elevated adenosine, and immunosuppressive populations, further regulates this interaction by limiting NK cytotoxicity and promoting tumor resistance to ferroptosis. Preclinical studies indicate that combining ferroptosis inducers with NK cell-based immunotherapies yields synergistic antitumor effects. Additionally, genetically engineered NK cells designed to enhance tumor ferroptotic susceptibility represent a promising strategy to overcome immune evasion. This review summarizes recent discoveries on the NK-ferroptosis axis, delineates the molecular and cellular mechanisms governing their crosstalk in the TME, and explores therapeutic opportunities to leverage this pathway for cancer treatment. Understanding this regulatory network could inform the development of innovative immunometabolic interventions to improve current immunotherapy outcomes.