The immunomodulatory role of docosahexaenoic acid in limiting tumour growth depends on an improvement in NK cell effector functions (PRJCA024177)

The antitumour effects of ?-3 polyunsaturated fatty acids (PUFAs), which are known to directly repress tumour cells, have been extensively studied. In this study, we explored the immunomodulatory role of docosahexaenoic acid (DHA), a type of ?-3 PUFA, in promoting tumour growth in immunocompetent mice. The number of natural killer (NK) cells but not that of T or B cells was decreased by DHA supplementation in various tissues under physiological conditions. However, the frequency and number of NK cells were comparable, but IFN-? production by NK cells in both the spleen and lung was increased in DHA-supplemented mice in a mouse tumour model of B16F10 melanoma cells. Single-cell RNA sequencing (scRNA-seq) revealed that DHA promoted effector function and oxidative phosphorylation in NK cells but had no obvious effects on other immune cells. Using Rag2-/- mice and a NK cell depletion model established by PK136 antibody injection, we demonstrated that the suppression of B16F10 melanoma tumour growth in the lung by DHA supplementation was dependent mainly on NK cells. In vitro experiments showed that DHA directly enhanced IFN-? production, CD107a expression and mitochondrial oxidative phosphorylation (OXPHOS) activity and slightly increased proliferator-activated receptor gamma coactivator-1a (PGC-1a) protein expression in NK cells. The PGC-1a inhibitor SR-18292 in vitro and NK cell-specific knockout of PGC-1a in mice reversed the antitumour effects of DHA. In summary, our findings broaden the current knowledge on how DHA supplementation protects against cancer growth from the perspective of immunomodulation by upregulating PGC-1a signalling-mediated mitochondrial OXPHOS activity in NK cells.