Fig. 3

Targeting signalling to support NK metabolism in the TME. Metabolically adverse TME can be the result of excess nutrients such as fatty acids and cholesterol/oxysterols that can lead to the activation of PPAR and the inhibition of SREBP in NK cells, respectively. Other factors in the TME including tumour growth factor beta (TGF-β), pH, lactate has been shown to interfere with metabolic signalling in NK cells (not shown). Insufficient nutrients, including glucose and amino acids, will inhibit the activity nutrient sensors such as cMyc and mTORC1 in NK cells. Such alterations in NK signalling negatively affect NK cell metabolism, including flux through glycolysis and OXPHOS and in doing so impair NK cell anti-tumour responses. Strategies to improving NK cell function within the TME could involve boosting (*) or inhibiting (#) the relevant signalling pathway corresponding to the metabolic conditions within the TME