Fasting reshapes tissue-specific niches to improve the innate immune response to cancer

Fasting has long been associated with the improved elimination of cancer cells. However, the distinctive role of specific immune subsets mediating these anti-tumor properties remain elusive. Using a cyclic fasting diet (CFD) after tumor initiation, we investigated the impact of fasting on NK cell anti-tumor immunity. We found that adherence to a CFD improved anti-tumor immunity against both solid and metastatic tumors in a NK cell-dependent manner. During periods of fasting, NK cells underwent tissue redistribution where NK cells in the spleen experienced tissue-specific metabolic rewiring. These NK cells were exposed to elevated concentrations of fatty acids and glucocorticoids which increased fatty acid metabolism via expression of CPT1A, and was essential for NK cell survival and anti-tumor functions. In parallel, a population of NK cells were redistributed to the bone marrow during CFD in a S1PR5- and CXCR4-dependent manner. These cells were primed by an increased pool of IL-12-expressing myeloid cells which improved IFN-g production. Together, these data uncover a novel dietary strategy to improve tumor clearance and identifies a previously unknown mechanistic link between dietary restriction and optimized innate immune responses. Natural Killer (NK) cells from the bone marrow, spleen and tumors of mice subjected to ad libitum or cyclic fasting diet conditions were isolated using fluorescence-activated cell sorting (FACS) and subjected to scRNA-seq.