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Updated: Jun 27, 2026
Flow Cytometry-Based Isolation and Therapeutic Evaluation of Tumor-Infiltrating Lymphocytes in a Mouse Model of Pancreatic Cancer
Published on: January 17, 2025
Targeting DGAT1 reprograms lipid landscape and restores CD8⁺ T cell immunity in pancreatic cancer
Zhongkun Liu1,2,3, Lang Chen1,2,3, Tong Zhang4
1Department of Colorectal Surgery & Oncology of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
Abstract:
Lipid accumulation is a hallmark of the pancreatic ductal adenocarcinoma (PDAC) tumor microenvironment, yet effective strategies to reprogram this lipid-rich niche and restore anti-tumor immunity remain limited. Here, we show that diacylglycerol O-acyltransferase 1 (DGAT1) as a tumor-intrinsic metabolic checkpoint that promotes immune evasion. DGAT1 inhibition rewires tumor lipid metabolism by promoting increased fatty acid uptake and redistribution, thereby depleting extracellular free fatty acids that impair CD8⁺ T cell function. Mechanistically, decreased palmitate availability alleviates endoplasmic reticulum stress, preserves FOXO1 activity, and supports stem-like CD8⁺ T cell differentiation. This competitive lipid remodeling enhances memory potential, restrains terminal exhaustion, and sensitizes PDAC tumors to PD-1 checkpoint blockade in vivo. Together, our findings identify tumor-immune lipid crosstalk as a key barrier to effective immunity in PDAC and establish DGAT1 as a promising therapeutic target to restore T cell function and improve immunotherapy response.
Insights
In pancreatic cancer, blocking DGAT1 enzyme reprograms tumor lipids to enhance anti-tumor CD8+ T cell function. This approach improves immunotherapy response by reducing immune evasion in the tumor microenvironment.
Area of Science:
- Oncology
- Immunology
- Metabolic Research
Background:
- Pancreatic ductal adenocarcinoma (PDAC) features a lipid-rich tumor microenvironment that hinders anti-tumor immunity.
- Current strategies to modify this niche and restore immune function are limited.
Purpose of the Study:
- To investigate the role of diacylglycerol O-acyltransferase 1 (DGAT1) in PDAC immune evasion.
- To explore DGAT1 inhibition as a therapeutic strategy to enhance anti-tumor immunity and immunotherapy response in PDAC.
Main Methods:
- Inhibition of DGAT1 in PDAC models.
- Analysis of tumor lipid metabolism and fatty acid uptake.
- Assessment of CD8+ T cell function, including differentiation and exhaustion markers.
- Evaluation of tumor response to PD-1 checkpoint blockade in vivo.
Main Results:
- DGAT1 inhibition altered tumor lipid metabolism, increasing fatty acid uptake and depleting extracellular free fatty acids.
- Reduced free fatty acids improved CD8+ T cell function by alleviating endoplasmic reticulum stress and preserving FOXO1 activity.
- DGAT1 inhibition promoted stem-like CD8+ T cell differentiation, enhancing memory potential and reducing exhaustion.
- Combined DGAT1 inhibition and PD-1 blockade demonstrated synergistic anti-tumor effects in vivo.
Conclusions:
- Tumor-intrinsic DGAT1 is a critical metabolic checkpoint promoting immune evasion in PDAC.
- Targeting DGAT1 can reprogram the tumor lipid metabolism to restore CD8+ T cell function.
- DGAT1 inhibition represents a promising strategy to overcome immunotherapy resistance in pancreatic cancer.
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