Lipid metabolism gene ECI2 affects neutrophil extracellular traps by inhibiting ether lipid production to suppress colorectal cancer invasion and metastasis

Abstract Abnormalities in ether lipid metabolism as well as neutrophil extracellular trap formation are recently identified as adverse factors affecting tumorigenesis and progression. However, the role of abnormal ether lipid metabolism in colorectal cancer (CRC) evolution has not been reported. Here, we show that the lipid metabolism-related gene, enoyl-CoA delta isomerase 2 (ECI2), plays a tumor-suppressive role in CRC and is negatively associated with poor prognosis in CRC patients. Mechanistically, we demonstrate that ECI2 inhibits ether lipogenesis by restraining the peroxisomal localization of AGPS, the rate-limiting enzyme in ether lipid synthesis. This subsequently suppresses IL-8-mediated neutrophil recruitment and extracellular trap formation, ultimately leading to inhibition of CRC proliferation and metastasis. These findings not only enhance our comprehension of the role of metabolic reprogramming and neutrophil interactions in CRC development, but also offer novel insights for identifying potential diagnostic markers and therapeutic targets for CRC.