Significance Eicosanoid and cytokine storms are poorly characterized in cancer. Our study demonstrates the environmental carcinogen aflatoxin B ₁ (AFB ₁ ) promotes hepatocellular carcinoma (HCC) by triggering a debris-stimulated proinflammatory and proangiogenic “eicosanoid and cytokine storm” in the tumor microenvironment. The dual COX-2/sEH inhibitor PTUPB prevents AFB ₁ -stimulated HCC growth by increasing macrophage phagocytosis of debris and suppressing the eicosanoid and cytokine storm, thus promoting resolution of inflammation. Enhancing endogenous clearance of debris via eicosanoid regulation, such as dual inhibition of COX-2/sEH, is a strategy to stifle inflammation and thus suppress tumor progression driven by carcinogens. sEH and dual COX-2/sEH inhibitors are in clinical development for multiple inflammatory diseases and thus may be rapidly translated for the prevention and treatment of carcinogen-induced cancers.