CYP4F2-Catalyzed Metabolism of Arachidonic Acid Promotes Stromal Cell-Mediated Immunosuppression in Non-Small Cell Lung Cancer

Fatty acid synthesis facilitates tumor cell immune escape and immunotherapy resistance. Cytochrome P450 (CYP) 4A and 4F, the major ω-hydroxylases that convert arachidonic acid (AA) into 20-hydroxyeicosatetraenoic acid (20-HETE), are implicated in inflammation and cancer. However, the role of CYP4 ω-hydroxylases in immune evasion remains unclear. Here, we determined that 20-HETE derived from the CYP4F2 isoenzyme governs immune evasion in non–small cell lung cancer (NSCLC) in a CD8+ T-cell-dependent manner. Mechanistically, CYP4F2 induced expression of immune checkpoint PD-L1 and production of proangiogenic factors IL6 and TGFβ in cancer-associated fibroblasts (CAF) via the 20-HETE-GPR75-STAT3-c-Jun axis. Tumors with high CYP4F2 expression were more resistant to anti-PD-1 treatment, whereas inhibition of CYP4F2 enhanced the efficacy of anti-PD-1 therapy in human NSCLC organoids and mouse models. Collectively, these data delineate that CYP4F2-dependent AA metabolism controls CAF-mediated immune evasion. CYP4F2 inhibition combined with PD-1 antibody represents a promising therapeutic approach for immunotherapy-resistant lung cancer. Significance: The identification of a role for CYP4F2-dependent metabolism in driving immune evasion in non–small cell lung cancer reveals a strategy to improve the efficacy of immunotherapy by inhibiting CYP4F2. See related article by Van Ginderachter, p. 3882