Fig. 3: Non-exhaustive scheme of lipid exchanges between tumor cells and tumor microenvironment (TME) cells and lipid reprogramming of stromal cells, that activate their pro-tumoral features.

Cancer-associated fibroblasts (CAFs) take up free fatty acid (FFAs), produce various lipids and together with cancer-associated adipocytes (CAAs) produce extracellular vesicles (EVs) that reach tumor cells to supply them with metabolic intermediates and enzymatic arsenal to activate metabolic pathways, such as fatty acid oxidation (FAO). CAAs are the seat of activated lipolysis, and the resulting FFAs once released in the TME can be taken up by tumoral cells. In tumor-associated macrophages (TAMs), the decreased in lipid rafts domains, resulting from increased cholesterol efflux, participate to TAMs activation. In these cells, prostaglandin E₂ (PGE₂) synthesis is also activated and contribute to the generation of an immunosuppressive tumor microenvironment. This latter is also promoted by myeloid-derived-suppressor cells (MDSCs), through the activation of FFA uptake and degradation and of the PGE₂-PGE₂ receptor 2 subtype (EP2) signaling pathway. Tumor cells are the recipients of various lipid species released in the TME by TME cells and are the mediators of an immunosuppressive TME via their release of lipids and cytokines. TAG triacylglycerides, TCA tricarboxylic acid, LPA lysophosphatidic acid, LPC lysophosphatidylcholine, ATX autotaxin, ETC electron transport chain, FA-CoA fatty acyl-Coenzyme A, LD lipid droplets, Gln glutamine, Glc glucose, SL sphingolipids, AA amino acids, lysoPL lysophospholipids, G-CSF granulocyte-colony stimulating factor, GM-CSF granulocyte macrophage colony stimulating factor, NO nitrogen oxide, 5-HETE 5-dydroxyeicosatetraenoic acid, LTB₄ leukotriene B₄, HB-EGF Heparin-binding EGF-like growth factor, TNFα tumor necrosis factor α, LDLR low-density lipoprotein receptor, PD-L1 programmed cell death-ligand 1, ABCA1 ATP Binding Cassette Subfamily A Member 1, ABCG1 ATP Binding Cassette Subfamily G Member 1. Indirect reaction is illustrated by dotted arrow and direct reaction by solid arrow.