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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, \u03c96, 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, \u03c93, 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.<\/jats:p>","DOI":"10.1021\/acsptsci.6c00098","type":"journal-article","created":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T18:01:42Z","timestamp":1786730502000},"page":"2482-2496","source":"Crossref","is-referenced-by-count":0,"title":["The Lipid Switch:\nUltra-High Dose Omega Fatty Acids\nDetermine\n                    <i>MYCN<\/i>\n                    Neuroblastoma Fate and Implicate Substrate-Level\nOxylipin Competition"],"prefix":"10.1021","volume":"9","author":[{"given":"Vishwa","family":"Patel","sequence":"first","affiliation":[{"name":"The University of Texas at Austin , , , ,","place":["Austin, Texas, United States, 78712"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan Ning","family":"Li","sequence":"additional","affiliation":[{"name":"The University of Texas at Austin , , , ,","place":["Austin, Texas, United States, 78723"]},{"name":"The University of Texas at Austin , , , ,","place":["Austin, Texas, United States, 78723"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Shen","sequence":"additional","affiliation":[{"name":"The University of Texas at Austin , , , ,","place":["Austin, Texas, United States, 78712"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9494-4245","authenticated-orcid":true,"given":"J. 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