Fatty acids modulate the colorectal cancer immune microenvironment via regulating the interaction and transactivation of PPARα/δ and P53

Dietary fatty acids accelerate cancer development and metastasis by altering the tumor microenvironment (TME), yet the mechanism is unclear. Here, two-sample Mendelian randomization (MR) revealed that BMI impairs colorectal cancer (CRC) immune surveillance. Additionally, a high-fat diet (HFD) reshapes the immunosuppressive TME, hallmarked by increased myeloid-derived suppressor cells and decreased CD8⁺ T cells in mice. Mechanistically, the unhealthy fatty acid palmitic acid (PA) binds to its nuclear receptors, peroxisome proliferator-activated receptors (PPARs), enhancing PPARδ while inhibiting PPARα and P53 transactivation, thereby upregulating CD73 and downregulating tumor necrosis factor-related apoptosis-inducing ligand receptors 1 and 2 (TRAIL-R1/2), which drives immunosuppression in CRC transplant tumors. Conversely, conjugated linoleic acid (CLA), a healthy fatty acid, enhances PPARα and P53 transactivation while inhibiting PPARδ transactivation, leading to decreased CD73 and increased TRAIL-R1/2, which enhances anti-tumor immunity and limits metastasis. These findings suggest a direct, universal mechanism by which fatty acid composition regulates immune homeostasis and tumor progression via PPARα/δ-P53 crosstalk.