Oesophagogastric adenocarcinomas (OAC) are obesity-associated malignancies, underpinned by severe immune dysregulation. We have previously shown that natural killer (NK) cells preferentially migrate to OAC omentum, where they undergo phenotypic and functional alterations and apoptosis. Furthermore, we have identified the CX3CR1:fractalkine (CX3CL1) pathway as pivotal in their recruitment to omentum. Here, we elucidate whether exposure to the soluble microenvironment of OAC omentum, and in particular fractalkine and IL-15 affects NK cell homing capacity towards oesophageal tumour. Our data uncover diminished NK cell migration towards OAC tumour tissue conditioned media (TCM) following exposure to omental adipose tissue conditioned media (ACM) and reveal that this migration can be rescued with CX3CR1 antagonist E6130. Furthermore, we show that fractalkine has opposing effects on NK cell migration towards TCM, when used alone or in combination with IL-15 and uncover its inhibitory effects on IL-15-mediated stimulation of death receptor ligand expression. Interestingly, treatment with fractalkine and/or IL-15 do not significantly affect NK cell adhesion to MAdCAM-1, despite changes they elicit to the expression of integrin α4β7. This study provides further evidence that CX3CR1 antagonism has therapeutic utility in rescuing NK cells from the deleterious effects of the omentum and fractalkine in OAC, thus limiting their dysfunction.Keywords: IL-15; chemokines; fractalkine; natural killer cell; oesophageal cancer.