Targeting Strategies for Aberrant Lipid Metabolism Reprogramming and the Immune Microenvironment in Esophageal Cancer: A Review

Abstract

Esophageal cancer is of high importance to occurrence, development, and treatment resistance. As evidenced by recent studies, pathways (e.g., Wnt/β-catenin, AMPK, and Hippo) are critical to the proliferation, differentiation, and self-renewal of esophageal cancer. In addition, the above pathways play a certain role in regulating esophageal cancer and act as potential therapeutic targets. Over the past few years, the function of lipid metabolism in controlling tumor cells and immune cells has aroused extensive attention. It has been reported that there are intricate interactions between lipid metabolism reprogramming between immune and esophageal cancer cells, whereas molecular mechanisms should be studied in depth. Immune cells have been commonly recognized as a vital player in the esophageal cancer microenvironment, having complex crosstalk with cancer cells. It is increasingly evidenced that the function of immune cells in the tumor microenvironment (TME) is significantly correlated with abnormal lipid metabolism. In this review, the latest findings in lipid metabolism reprogramming in TME are summarized, and the above findings are linked to esophageal cancer progression. Aberrant lipid metabolism and associated signaling pathways are likely to serve as a novel strategy to treat esophageal cancer through lipid metabolism reprogramming.

Figure 1

Overview of fatty acid metabolism in esophageal cancer cells. Lipid uptake can be achieved through multiple routes. ACLY, ATP citrate lyase; ACC, acetyl-CoA carboxylase; FASN, fatty acid synthase; SCD1, stearoyl-CoA desaturase 1; ACSS2, acetyl-CoA synthetase 2; ACS, acyl-CoA synthetases; CPT1, carnitine palmitoyl transferase 1; MAGL, monoacylglycerol lipase. TGs/CE, triglycerides/cholesteryl esters; TAG, triacylglycerol; FAs, fatty acids; FAO, fatty acid oxidation; LDLR, low-density lipoprotein receptor; HMG-CoA, hydroxy-3-methylglutaryl-CoA; HMGCR, hydroxy-3-methylglutaryl-CoA reductase; HMGCS, 3-hydroxy-3-methylglutaryl coenzyme A synthase; LDs, lipid droplets; SREBPs, sterol regulatory element-binding proteins.

Figure 2

Targeting signaling pathways in EC. Schematic representation of the Wnt, Notch, AMPK, MAPK, and Hippo pathways in EC. Novel therapeutics (synthetic and natural) kill EC by targeting these signaling pathways or their components. GSK3β, glycogen synthase kinase 3β; DSH, Disheveled; APC, adenomatous polyposis coli; GGPP, geranylgeranyl pyrophosphate; YAP/TAZ, Yes-associated protein (YAP)/tafazzin (TAZ); JAK/STAT3, Janus kinase/signal transducers and activators of transcription 3; SIRT1, silencing information regulator 2-related enzyme 1 (sirtuin 1); HNF4A, hepatocyte nuclear factor 4 alpha; PGC1A, peroxisome proliferator-activated receptor gamma coactivator 1-alpha; PPAR-γ, peroxisome proliferator-activated receptor-γ; PI3K-Akt-mTOR pathway, the phosphatidylinositol 3-kinase (PI3K)-serine-threonine kinase (Akt)-mammalian target of rapamycin (mTOR) pathway; p38 MAPK, p38 mitogen-activated protein kinase; pre-SREBP, premature sterol regulatory element-binding protein; M-SREBP, mature sterol regulatory element-binding protein.

Figure 3

Lipid metabolism reprogramming in the esophageal cancer microenvironment affects the anti‐/pro‐tumoral functions of immune cells. MDSC, marrow-derived suppressor cells; DCs, dendritic cells; FAO, fatty acid oxidation; FAS, fatty acid synthesis; TAMs, tumor-associated macrophages; FFA, free fatty acid; Tregs, regulatory T cells; NK Natural killer cells; AMPK, AMP-activated protein kinase; IL-10, interleukin 10; TGF-β, transforming growth factor-β; STAT3, transcription 3; LPL, lipoprotein lipase; NF-κB, nuclear factor; FABPs, fatty acid-binding proteins; LRP4, lipoprotein receptor-related protein 4; PPAR, peroxisome proliferator-activated receptors.