Extracellular Metabolites and Natural Killer Cell Antitumor Function: Mechanisms and Therapeutic Strategies

Natural killer (NK) cells are innate cytotoxic lymphocytes capable of eliminating malignant cells independent of prior antigen sensitization, thereby constituting a critical first-line defense in tumor immunosurveillance. Within the tumor microenvironment (TME), metabolic dysregulation profoundly impairs NK cell effector function, and accumulating studies have investigated the regulatory effects of extracellular metabolites on NK cells. This review systematically delineates the direct mechanistic interplay between extracellular metabolites and NK cell antitumor immunity, with particular emphasis on their roles as structural components, bioenergetic substrates, metabolic reprogramming inducers, modification donors, gene transcription regulators, stress response mediators, intracellular pH modulators, and ligands engaging cognate receptors to initiate downstream signaling cascades. Furthermore, we discuss the therapeutic strategies targeting metabolites to potentiate NK cell functionality, encompassing modulation of metabolite availability within the TME and exploitation of metabolite-sensitive signaling axes. In addition, combination of metabolic interventions with other modalities, such as adoptive NK cell transfer and anti-programmed cell death protein 1/programmed death-ligand 1 therapy, is also evaluated for prospective applications. This review provides a conceptual framework for understanding the metabolic regulation of NK cells, highlighting emerging directions for advancing NK-cell-centered cancer immunotherapy through metabolic modulation.