Project Summary Obesity has reached epidemic proportions globally with the biggest heath and economic burden being the many obesity-related diseases. Among these diseases, obesity is a strong risk factor for cancer, accounting for up to 49% of certain cancers. It is expected that obesity will soon replace smoking as the leading preventable cause of cancer. Despite increased public awareness and prevention strategies, the prevalence of obesity and related diseases continue. Therefore there is increased urgency to understand the pathways whereby obesity leads to other diseases, and to develop new strategies prevent their progression. It is now appreciated that obesity is associated with immune dysregulation, which may be the cause of some obesity related diseases. Natural killer (NK) cells are so-called due to their natural cytotoxicity against tumors cells. We have previously shown that obese individuals have reduced NK cell numbers and the remaining NK cells are unable to kill tumors cells efficiently. The key unanswered questions are 1) how does obesity induce NK cell defects, 2) Does NK cell impairment increase the risk of cancer in obesity, and 3) Can obesity induced immune dysfunction be reversed or prevented. This project will use a multi-disciplinary approach to decipher if epigenetic and metabolic changes in NK cells in obesity lead to their inability to survey and kill tumors. Immunometabolism is rapidly becoming an area of huge potential for treating disease, however much is still to be discovered. Results from this project will yield new insight into the complex changes that occur in innate immune cells in obesity and how they affect immune surveillance. It will also reveal a largely unexplored intersection between metabolic pathways and epigenetic modifications in the immune system. Our preliminary data shows that the effect of obesity is analogous to rapamycin treatment in terms of the effect on dampening NK cell functions. This likely impacts the ability of the innate immune system to act upon foreign or damaged cells when they encounter them, and may at least partly explain the increased risk of infection and cancer in obese individuals.