Fig. 3
Lipids differentially affect immune populations while overall promoting an immunosuppressive phenotype. Lipids have emerged as an enemy of an antitumor environment because they suppress cytotoxic antitumor NK and CD8 T cells while promoting the survival and protumorigenic roles of Tregs and γδ17 cells. In the presence of FAs, NK cells display increased expression of the scavenger receptor CD36, which leads to the accumulation of intracellular lipids. In response to lipids, NK cells activate a PPAR-dependent lipid metabolism transcriptional program, which leads to the inhibition of the mTORC1 protein complex. Loss of mTORC1 signaling results in a state of metabolic paralysis, resulting in reduced cytotoxicity and impaired IFNγ and granzyme B production. CD8 T cells also display increased expression of CD36 and markers of functional exhaustion, including PD-1 and TIM-3, in lipid-rich tumor environments. In addition to FAs, CD8 T cells may also transport OxLDL through CD36, which enhances lipid peroxidation, resulting in ferroptosis. Together, these metabolic adaptations to a lipid-rich environment result in impaired functional responses and cultivate a protumorigenic environment. On the other hand, lipid uptake and synthesis have been shown to promote Treg immunosuppression in many tumor models. Intratumoral Tregs display heightened expression of CD36, which provides lipids to activate a PPAR-dependent lipid metabolism program that is essential for their survival, proliferation and protumor functions. Intratumoral Tregs also increase the expression of SREBPs, leading to the de novo synthesis of FAs and cholesterol. Similarly, protumorigenic γδ17 cells rely on lipid uptake and metabolism to regulate IL-17 production. γδ17 cells display increased mitochondrial mass and potential to support heightened rates of lipid metabolism. IL-17 is important for promoting neutrophil-mediated cancer metastasis, highlighting the role of lipids in promoting primary and metastatic cancer progression
