Multidimensional plasticity of natural killer cells in tumours

Natural killer (NK) cells exhibit remarkable adaptability within the tumour microenvironment (TME), where dynamic shifts in phenotype, function and metabolism govern their dual roles in antitumour immunity and tumour immune evasion. In the TME, NK cells undergo receptor remodelling, which is characterised by upregulated inhibitory signals and suppressed activating receptors, leading to the formation of dysfunctional subsets, such as exhausted TIM-3⁺ NK cells or tissue-resident CD49a⁺ populations. Immunosuppressive factors within the TME drive a transition from cytotoxic activity to regulatory or senescent-like states, impairing tumour surveillance. Metabolic reprogramming further compromises NK cell effector functions, as nutrient deprivation and metabolic byproducts disrupt energy pathways and suppress immune responses. Therapeutic strategies targeting this plasticity include engineered natural killer (NK) cells with enhanced specificity, metabolic restoration approaches and microenvironment-modulating interventions. However, challenges persist because of TME heterogeneity and persistent dysfunctional states. Understanding these adaptive mechanisms provides a framework for developing NK cell-based therapies that leverage plasticity to counteract tumour resistance.