# CYP4X1/sEH‐Dependent Endocannabinoid Metabolism Drives Fibroblast‐Mediated Immunosuppression to Limit Immunotherapy in Colon Cancer

## TL;DR

This study shows that CYP4X1 and sEH enzymes help colon cancer cells avoid immune detection by promoting immune-suppressing cells and reducing T cell activity, suggesting a new way to improve cancer immunotherapy.

## Contribution

The study identifies a novel mechanism by which CYP4X1/sEH-dependent endocannabinoid metabolism promotes immune evasion in colon cancer through fibroblast-mediated immunosuppression.

## Key findings

- CYP4X1/sEH metabolism increases regulatory T cells and reduces CD8+ T cell function in colon cancer.
- The CYP4X1/sEH-GPR119 axis upregulates PD-L1, CXCL12, and TGF-β in cancer-associated fibroblasts.
- Targeting the CYP4X1/sEH-GPR119 axis improves anti-PD-1 therapy efficacy in colon cancer.

## Abstract

Cytochrome P450 (CYP) 4X1 and soluble epoxide hydrolase (sEH), the key enzymes responsible for endocannabinoid oxidative metabolism, have been implicated in inflammation and cancer. However, the precise role of CYP4X1 and sEH in tumor immune evasion is poorly understood. Here, it is elucidated that CYP4X1/sEH‐dependent endocannabinoid metabolism governs immune evasion in colon cancer by promoting the infiltration of regulatory T cells (Tregs) and impairing CD8+ T cell effector function. Mechanistically, CYP4X1/sEH‐derived 14,15‐EET‐EA upregulates PD‐L1, CXCL12, and TGF‐β in cancer‐associated fibroblasts (CAFs) via the GPR119‐Gs/β‐arrestin 2 signaling axis. Importantly, targeted regulation of the CYP4X1/sEH‐GPR119 axis enhances the efficacy of anti‐PD‐1 therapy. Moreover, CYP4X1 and sEH levels jointly predict prognosis and immune infiltration in human colon cancer. 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.

A proposed mechanism to explain the role of CYP4X1/sEH‐14,15‐EET‐EA system in colon cancer immune escape. 14,15‐EET‐EA, 14,15‐epoxyeicosatrienoic acid‐ethanolamide; sEH, soluble epoxide hydrolase; CYP4X1, cytochrome P450 4X1; GPR119, G‐protein coupled receptor 119; EGFR, epidermal growth factor receptor; Gs, Gαs subunit; cAMP, cyclic adenosine monophosphate; CXCL12, C‐X‐C motif chemokine 12; TGF‐β, transforming growth factor‐β; PD‐L1, programmed death ligand 1; CAFs, cancer‐associated fibroblasts.