It is proposed that the maintained production and availability of acetyl-CoA, an indicant of OXPHOS, is a determinant of glycolysis upregulation, with acetyl-CoA acting to regulate the many factors and intracellular pathways contributing to ‘exhaustion’, including TGF-β, adenosine A2Ar activation and AhR/COX2/PGE2/EP4 activation, as well as the effects of obesity and type II diabetes on cancer risk, which are partly driven by raised leptin levels priming cytolytic cells [7]. This evidence concerns the gene LEP and Obesity.