The Lipid Switch: Ultra-High Dose Omega Fatty Acids Determine MYCN Neuroblastoma Fate Through Oxylipin Competition

High-risk neuroblastoma (NB) remains a lethal pediatric cancer, and low-toxicity strategies are urgently needed. Using a syngeneic MYCN-driven model, we tested ultra-high dose oral arachidonic acid (ARA, ω6, 4.7 g/d hEq) and docosahexaenoic acid (DHA, ω3, 24 g/d hEq) as modifiers of tumorigenesis. ARA strikingly accelerated tumor growth, producing 100% tumor incidence and solid tumors without necrosis, and fourfold larger than controls. In contrast, DHA profoundly suppressed tumor progression: half of the tumors regressed completely, while the remainder grew slowly, averaging 4.5-fold smaller than controls and 18-fold smaller than ARA tumors. Lipid mediator profiling revealed mechanistic divergence, with ARA increasing angiogenic, proliferative, invasive, pro-inflammatory eicosanoids (PGE2, TXB2, EETs) and DHA enriching anti-inflammatory mediators (17,18-EpETE, 18-HEPE, 14-HDHA). Both treatments were well tolerated. These findings establish tissue lipid composition as a major determinant of neuroblastoma tumorigenesis, alongside genes and proteins, together suggesting DHA as a clinically tractable, safe adjunct to conventional therapies.