Together, this study highlights that CYP4X1/sEH-dependent endocannabinoid metabolism controls CAF-mediated immune evasion, and targeting the CYP4X1/sEH-14,15-EET-EA-GPR119 axis represents a promising therapeutic strategy for improving anti-PD-1 therapy in colon cancer. Here, EPHX2 is linked to malignant colon neoplasm.