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

  • Cell Rep. 2025 Nov 25;44(12):116623. doi: 10.1016/j.celrep.2025.116623.
Binyan Xu  1 ,  Xufeng Hou  2 ,  Maoyuan Wang  1 ,  Lin Qiu  1 ,  Xiling Chen  1 ,  Guoming Deng  1 ,  Daixuan Zhou  1 ,  Yun Feng  1 ,  Jinzhao Han  1 ,  Xiaojing Meng  3 ,  Hongying Fan  4 ,  Weisen Zeng  5 ,  Yang Bai  6
Affiliations
  • 1. Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Institute of Gastroenterology of Guangdong Province, Nanfang Hospital, Southern Medical University, Guangzhou, China.
  • 2. Department of Cell Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China; Beijing Youngen Technology Co., Ltd., No. 55 Qingfeng West Road, Daxing District, Beijing, China.
  • 3. Department of Occupational Health and Occupational Medicine, School of Public Health, Southern Medical University, Guangzhou 510515, Guangdong, China.
  • 4. Department of Microbiology, Guangdong Provincial Key Laboratory of Tropical Diseases Research, School of Public Health, Southern Medical University, Guangzhou, China. Electronic address: [email protected].
  • 5. Department of Cell Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China. Electronic address: [email protected].
  • 6. Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Institute of Gastroenterology of Guangdong Province, Nanfang Hospital, Southern Medical University, Guangzhou, China; Department of Huiqiao Medical Center, Nanfang Hospital, Southern Medical University, Guangzhou 510515, Guangdong, P.R. China. Electronic address: [email protected].
PMID: 41296567 DOI: 10.1016/j.celrep.2025.116623
Abstract

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.

Keywords
CP: cancer; CP: immunology; P53; fatty acid; immunoregulation; peroxisome proliferator-activated receptors; transactivation activity; tumor microenvironment.
Products
Inhibitors & Agonists
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-125286
    AB-680
    99.71%, CD73 Inhibitor
    target: CD73
    Research Areas: Cancer
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