2. Academic Validation
  3. Fatty acids modulate the colorectal cancer immune microenvironment via regulating the interaction and transactivation of PPARα/δ and P53

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

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.

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  • HY-125286
    99.71%, CD73 Inhibitor
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