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. 2022 Jul 7;10(7):e004584. doi: 10.1136/jitc-2022-004584

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© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See http://creativecommons.org/licenses/by-nc/4.0/.

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Influence of lipids on tumor infiltrating immune cells. Natural killer (NK) cells: a free fatty acid (FFA)-rich environment upregulates peroxisome proliferator–activated receptors PPARα and PPARδ, which in turn inhibit mammalian target of rapamycin (mTOR)-mediated pathways, including transcription of cytotoxic granules and interferon γ (IFN-γ), with deriving promotion of immune tolerance. Dendritic cells (DCs): lipid uptake through Msr1 receptor leads to accumulation of lipid droplets (LD), which are responsible for the defective translocation of major histocompatibility complex class I (MHC-I) complex to the cell surface, thus impairing DC antigen presentation and subsequent priming of CD8⁺ T cells’ antitumor activity. Likewise, fatty acid (FA) synthesis upon fatty acid synthase (FASN) upregulation can hamper correct DC functioning. CD4⁺ T helper cells: linoleic acid activates PPARα, whose downstream pathways determine the accumulation of reactive oxygen species (ROS), which in turn cause CD4⁺ T cell apoptosis. CD4⁺ regulatory T (Treg) cells: lipids enter the cell through transporters like CD36 (Cluster of differentiation 36), SLC7A1 (Solute Carrier Family 7 Member 1) and SLC7A4 (Solute Carrier Family 7 Member 7). Together with synthesized ones, lipids activate PPARβ that sustains mitochondrial activity and oxidative phosphorylation (OXPHOS), with FFAs as main substrate. This supports Treg survival and immunosuppressive functions. CD8⁺ cells: FFAs can impair cytotoxic activity by inducing upregulation of tumor-trophic genes (Opn), downregulation of cytotoxic genes (Ifng and Gzmb) and programmed cell death protein 1 (PD-1) expression. Intake of FFAs can be mediated by CD36 with downstream pathways impairing cell functionality, like lipid peroxidation and ferroptosis. In contrast with this, CD46 transmembrane molecule can increase FASN, FABP5 (Fatty acid binding protein 5) and SLC7A5 (Solute Carrier Family 7 Member 5) levels, thus promoting FFA intake and metabolism. FFAs induce PPARα activation, with subsequent support to mitochondrial activity that promotes release of molecules like IFN-γ. CD46 is also responsible for mTOR-mediated FA reprogramming, which is essential for CD8⁺ T cells’ effector function and survival.