The Lipid Switch:Ultra-High Dose Omega Fatty AcidsDetermine <i>MYCN</i> Neuroblastoma Fate and Implicate Substrate-LevelOxylipin Competition

Abstract Pediatric neuroblastoma exhibits puzzling biological heterogeneity─some tumors regress spontaneously while high-risk cases resist intensive multimodal therapy─suggesting modifiable determinants of tumor fate beyond genes and proteins. Using a syngeneic MYCN-driven mouse model, we show that lipid composition acts as a switch, creating chemical environments that determine neuroblastoma progression implicating competing oxylipin signaling pathways. Ultrahigh dose oral arachidonic acid (ARA, ω6, 4.7 g/day human equivalent) dramatically accelerated tumorigenesis, producing 100% tumor incidence with solid non-necrotic masses 4-fold larger than controls. Conversely, docosahexaenoic acid (DHA, ω3, 24 g/day equivalent) profoundly suppressed tumor progression: half of the tumors regressed completely, while the remainder grew slowly, averaging 22% the size of controls and 6% the size of ARA tumors. Comprehensive oxylipin profiling via LC-MS/MS revealed divergent oxylipin profiles: ARA metabolism via cyclooxygenase, lipoxygenase, and cytochrome P450 pathways generated pro-tumorigenic eicosanoids (PGE2, TXB2, EETs) that drive angiogenesis, tumor cell proliferation, and invasion. In contrast, DHA competitively suppressed ARA-derived eicosanoid synthesis while enriching tissues with anti-inflammatory, pro-resolving mediators (17,18-EpETE, 18-HEPE, 14-HDHA) that inhibit pathological angiogenesis and tumor growth. Both treatments were well tolerated in our model at projected doses safe in adult humans for other indications. Because COX/LOX/CYP450-mediated oxylipin signaling operates across solid tumors, these findings support dietary highly unsaturated fatty acid composition as a candidate, modifiable determinant of cancer progression, suggesting ultrahigh dose omega-3 fatty acids as a low-toxicity adjunct to conventional therapies.