Table 4 Three types of plasticity of NK cells.

Phenotypic plasticity

1. Reprogramming: Inhibitory receptors (TIGIT, TIM-3⁺, PD-1) are upregulated, while activating receptors (NKG2D⁺, DNAM-1⁺) are downregulated；

2. Epigenetic silencing: High methylation of the NKG2D⁺ promoter, HDAC-mediated chromatin compaction of DNAM-1⁺；

3. Subgroup heterogeneity: The hypoxic area is enriched with TIM-3⁺-depleted subgroups and the tissue-resident CD49a⁺ subgroups

1. Loss of target recognition ability

2. Impaired formation of immune synapses

3. Persistent functional impairment

1. Receptor engineering: TIGIT/PD-1 blockers

2. Epigenetic intervention: HDAC inhibitors

3. Subgroup targeting: TIM-3⁺ antibody combination therapy

1. Exhaustive type: TIM-3⁺, PD-1⁺, LAG-3⁺

2. Tissue-resident type: CD49a⁺, CD103⁺, CXCR6⁺

3. Immunosuppressive type: CD39⁺, CD73⁺, A2AR⁺

1. Colorectal cancer, liver cancer (TIM-3⁺ depleted type)

2. Non-small cell lung cancer (CD39⁺CD73⁺ immunosuppressive type)

3. Glioblastoma (CD49a⁺ tissue-resident type)

[12, 14, 17, 25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47]

Functional plasticity

1. TGF-β/SMAD3 pathway: recruits HDAC to silence toxic genes (TBX21, PRF1);

2. Metabolic stress: lactic acid inhibits the mTORC1/NFATc1 pathway, reducing IFN-γ production;

3. Spatial polarisation: the tumour margin is enriched with IFN-γ⁺ toxic subpopulations, while the hypoxic core is enriched with PD-L1⁺ immunosuppressive subpopulations.

1. Transformation from cytotoxicity to immunosuppression

2. Decreased ADCC function

3. Loss of immune surveillance function

1. Immune checkpoint blockade: Anti-PD-L1 antibody

2. Metabolic reversal: Lactate dehydrogenase inhibitor

3. Spatial targeted delivery: Hypoxia-responsive drug carrier

1. Function exhaustion: CD107a⁺ (decreased particle release), IFN-γlow

2. Regulatory phenotype: CD56brightCD16⁻, IL-10⁺

3. Angiogenesis-related: VEGF⁺, IL-10⁺

1. Triple-negative breast cancer (mitochondrial dysfunction induced by TGF-β)

2. EBV-related gastric cancer (reduced IFN-γ secretion of TIM-3⁺ NK cells within the tumour)

3. Glioblastoma (secretion of VEGF by CD56brightCD16⁻ cells)

[38, 48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72]

Metabolic plasticity

1. Energy crisis: Lactic acid accumulation inhibits OXPHOS, while AMPK drives glycolysis;

2. Nutritional competition: Tryptophan depletion activates the IDO-AHR pathway, inhibiting mTORC1;

3. Lipid metabolism disorder: Cholesterol enrichment enhances the cytotoxicity of liver cancer NK cells, but oxysterol induces dysfunction.

4. Metabolic memory: The H3K27ac histone mark redistributes from toxic genes to tolerant genes.

1. Mitochondrial function impairment (TOMM20 ↓)

2. Decreased secretion of granzyme B

3. Chronic metabolic adaptation leading to persistent failure

1. Metabolic intervention: NAD⁺ supplementation, IDO inhibitors (Epacadostat)

2. Lipid metabolism targeting: CPT1A agonists/inhibitors (depending on tumour type)

3. Artificial metabolic support: Ketone body to enhance mitochondrial efficiency

1. Mitochondrial dysfunction: TOMM20 is low

2. Lipid accumulation type: Lipid droplet enrichment, CPT1A⁺ (related to fatty acid oxidation)

3. Metabolic stress type: AMPK activation, mTORC1 inhibition

1. Breast cancer (mitochondrial dysfunction induced by TGF-β)

2. EBV-positive gastric cancer (lipid accumulation in hypoxic areas of NK cells)

3. Acute myeloid leukaemia (NAD⁺ supplementation can improve the function of CAR-NK cells)

[50, 64, 73,74,75,76,77,78,79,80,81,82]

Cross-dimensional synergy

1. Epigenetic modifications stabilise metabolic and functional defects;

2. Downregulation of receptors and metabolic inhibition form a positive feedback loop (such as TIGIT inhibiting NKG2D⁺ endocytosis);

3. Spatial heterogeneity (hypoxia/normal oxygenation) drives the coordinated dysregulation of phenotype, function and metabolism.

1. Multidimensional paralysis: Failure of the entire chain from recognition to activation to effectuation.

2. Immunosuppressive microenvironment self-reinforcement

1. Combined therapy: CAR-NK+TGF-β inhibitor + metabolic regulator

2. Microenvironment remodelling: targeting CD73⁺ (adenosine signal), oHSV-CXCL10 virus

1. Composite marker: TIM-3⁺TOMM20low (depletion + mitochondrial abnormalities)

2. CD39⁺CD73⁺PD-1⁺ (immunosuppression + functional exhaustion)

3. CD49a⁺Lipid droplet⁺ (tissue residence + metabolic accumulation)

1. Hepatocellular carcinoma (CD155-TIGIT axis activates and simultaneously inhibits glycolysis and cytotoxicity)

2. Non-small cell lung cancer (CD39⁺CD73⁺ NK cells inhibit T cells through the adenosine pathway, while themselves suffer from impaired metabolic constraint function)

3. Glioblastoma (CD49a⁺ resident NK cells undergo metabolic reprogramming due to hypoxia, with increased VEGF secretion and loss of killing function)

[15, 66, 73, 83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,99,100,101,102,103,104,105,106,107,108,109,110,111,112,113,114,115]