The ω-3 Polyunsaturated Fatty Acid Docosahexaenoic Acid Enhances NK-Cell Antitumor Effector Functions

Abstract

ω-3 polyunsaturated fatty acids (PUFAs) are known to directly repress tumour development and progression. In this study, we explored whether docosahexaenoic acid (DHA), a type of ω-3 PUFA, had an immunomodulatory role in promoting tumour growth in immunocompetent mice. The number of natural killer (NK) cells but not the number of T or B cells was decreased by DHA supplementation in various tissues under physiological conditions. Although the frequency and number of NK cells were comparable, IFN-γ production by NK cells in both the spleen and lung was increased in DHA-supplemented mice in the mouse B16F10 melanoma tumour model. 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 NK-cell depletion 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-γ production, CD107a expression and mitochondrial oxidative phosphorylation (OXPHOS) activity, and slightly increased proliferator-activated receptor gamma coactivator-1α (PGC-1α) protein expression in NK cells. The PGC-1α inhibitor SR-18292 in vitro and NK cell–specific knockout of PGC-1α 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-1α signalling–mediated mitochondrial OXPHOS activity in NK cells.

Cellular Basis of Adjuvant Role of n-3 Polyunsaturated Fatty Acids in Cancer Therapy: Molecular Insights and Therapeutic Potential against Human Melanoma

“…For instance, DHA has been shown to induce apoptosis in cancer cells, regulate the cell cycle, and enhance the effectiveness of the immune system against tumor cells. Additionally, DHA can impact signaling pathways such as PI3K/Akt and modulate the expression of immune checkpoints [44][45][46][47]. However, while these findings are promising, comprehensive in silico analyses and simulations are needed to explore the specific mechanisms on melanoma cells.…”

Heterogenous causal effects of serum fatty acid levels on the risk of cerebral and abdominal aortic aneurysm: a Mendelian Randomization study

“…Pennington ER et al reported that the localization of DHA acyl chains to nonrafts is driving sphingomyelin and cholesterol molecules into larger lipid rafts and serve as a trigger to impede inflammation 14 . In addition, Wu S reported that DHA supplementation enhances the production of IFN-γ and mitochondrial oxidative phosphorylation 15 .…”