ECI2 drives melanoma progression via arachidonic acid metabolism and NETs-induced TLR3/COX2/PGE2 positive feedback loop

Melanoma is a highly malignant, metastatic skin tumor with complex progression mechanisms. This study reveals that the metabolic enzyme ECI2 is significantly overexpressed in melanoma tissues and is closely associated with poor patient prognosis. Functional experiments confirm that ECI2 significantly promotes the proliferation, migration, and invasive capabilities of melanoma cells both in vitro and in vivo. Mechanistic investigations reveal that ECI2 reshapes arachidonic acid metabolism in tumor cells, leading to the accumulation of the metabolite PGE2. These metabolites activate neutrophils, inducing the formation of neutrophil extracellular trap networks (NETs) via reactive oxygen species (ROS)-dependent pathways. Crucially, this study innovatively demonstrates that NETs are not the final effector. NETs activate the TLR3/COX-2/PGE2 axis in melanoma cells, establishing a metabolic-immune positive feedback loop. This circuitry persistently drives malignant tumor behavior, profoundly reshaping the tumor microenvironment. Our work not only proposes ECI2 as a key oncogene and potential therapeutic target but, more importantly, reveals a novel mechanism whereby tumor cells establish a positive feedback dialogue between metabolic reprogramming and innate immune effector NETs. This provides a novel theoretical framework for understanding melanoma progression and developing combined therapeutic strategies. Subject terms : ECI2, arachidonic acid metabolism, neutrophil extracellular traps, melanoma