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Peer-reviewedCC BY 4.0Frontiers in Oncology

Decoding lipid metabolic reprogramming in pancreatic ductal adenocarcinoma: from tumor–microenvironment crosstalk to therapeutic resistance

  • Xingyu Liu1
  • Zitong Ye2
  • Liuyang Wang3
  • Yubo Chi1
  • Tongjia Chu4
  • Ziyu Liu1
  • Shanxiang Yu1
  • Haocheng Yang1
  • Xinyue Yin5
  • Jian Zhang1
  • Alfred Wei Chieh Kow6,7,8,9
  • Huan Liu1
9 affiliations
  1. 1Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, The First Hospital of Jilin University
  2. 2The First Hospital of Jilin University
  3. 3Department of Colorectal & Anal Surgery, General Surgery Center, The First Hospital of Jilin University
  4. 4Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center
  5. 5Jilin University School of Public Health
  6. 6Division of Hepatobiliary & Pancreatic Surgery, Department of Surgery, National University Hospital Singapore
  7. 7Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore
  8. 8Division of Surgical Oncology, National University Cancer Institute Singapore (NCIS), National University Health System
  9. 9National University Digestive Center (NUCD), National University Health System Singapore
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Abstract

Pancreatic ductal adenocarcinoma (PDAC) is characterized by a nutrient-poor, hypoxic, and highly desmoplastic microenvironment that imposes substantial metabolic stress on malignant cells. Under these unfavorable conditions, lipid metabolism reprogramming provides cancer cells with the flexibility needed to maintain growth and survive therapeutic stress. Recent advances have uncovered new links between lipid metabolic reprogramming, the tumor microenvironment, and therapeutic resistance in PDAC, highlighting the need for an updated synthesis of this rapidly evolving field. In this review, we focus on the major tumor-intrinsic alterations in fatty acid and cholesterol–mevalonate metabolism, including changes in lipid synthesis, uptake, desaturation, storage, and oxidative utilization. These processes support membrane homeostasis, oncogenic signaling, and redox control, thereby linking lipid handling directly to tumor progression and treatment adaptation. We further review how these pathways are reshaped by the tumor microenvironment, where cancer-associated fibroblasts, immune cells, adipocytes, and neural-associated cells influence lipid availability, trafficking, and signaling. These reciprocal interactions can shape stromal plasticity, immune suppression, invasion, metastasis, and treatment response. We also evaluate current strategies targeting lipid metabolism and discuss why their clinical translation remains limited by metabolic compensation, tumor heterogeneity, drug specificity, and systemic toxicity. Overall, the available evidence suggests that lipid metabolism in PDAC is better understood as a dynamic, interconnected adaptive network rather than a set of isolated metabolic pathways. This perspective supports biomarker-guided combination strategies that target context-dependent lipid dependencies and treatment-induced metabolic adaptation, rather than relying on inhibition of a single pathway.

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Cite

BibTeXRIS
BibTeX
@article{liu2026decoding,
  title = {{Decoding lipid metabolic reprogramming in pancreatic ductal adenocarcinoma: from tumor–microenvironment crosstalk to therapeutic resistance}},
  author = {Xingyu Liu and Zitong Ye and Liuyang Wang and Yubo Chi and Tongjia Chu and Ziyu Liu and Shanxiang Yu and Haocheng Yang and Xinyue Yin and Jian Zhang and Alfred Wei Chieh Kow and Huan Liu},
  journal = {Frontiers in Oncology},
  year = {2026},
  month = oct,
  doi = {10.3389/fonc.2026.1977031},
  url = {https://www.frontiersin.org/articles/10.3389/fonc.2026.1977031/full},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Decoding lipid metabolic reprogramming in pancreatic ductal adenocarcinoma: from tumor–microenvironment crosstalk to therapeutic resistance
AU  - Xingyu Liu
AU  - Zitong Ye
AU  - Liuyang Wang
AU  - Yubo Chi
AU  - Tongjia Chu
AU  - Ziyu Liu
AU  - Shanxiang Yu
AU  - Haocheng Yang
AU  - Xinyue Yin
AU  - Jian Zhang
AU  - Alfred Wei Chieh Kow
AU  - Huan Liu
PY  - 2026
DA  - 2026/10/26
JO  - Frontiers in Oncology
DO  - 10.3389/fonc.2026.1977031
UR  - https://www.frontiersin.org/articles/10.3389/fonc.2026.1977031/full
AB  - Pancreatic ductal adenocarcinoma (PDAC) is characterized by a nutrient-poor, hypoxic, and highly desmoplastic microenvironment that imposes substantial metabolic stress on malignant cells. Under these unfavorable conditions, lipid metabolism reprogramming provides cancer cells with the flexibility needed to maintain growth and survive therapeutic stress. Recent advances have uncovered new links between lipid metabolic reprogramming, the tumor microenvironment, and therapeutic resistance in PDAC, highlighting the need for an updated synthesis of this rapidly evolving field. In this review, we focus on the major tumor-intrinsic alterations in fatty acid and cholesterol–mevalonate metabolism, including changes in lipid synthesis, uptake, desaturation, storage, and oxidative utilization. These processes support membrane homeostasis, oncogenic signaling, and redox control, thereby linking lipid handling directly to tumor progression and treatment adaptation. We further review how these pathways are reshaped by the tumor microenvironment, where cancer-associated fibroblasts, immune cells, adipocytes, and neural-associated cells influence lipid availability, trafficking, and signaling. These reciprocal interactions can shape stromal plasticity, immune suppression, invasion, metastasis, and treatment response. We also evaluate current strategies targeting lipid metabolism and discuss why their clinical translation remains limited by metabolic compensation, tumor heterogeneity, drug specificity, and systemic toxicity. Overall, the available evidence suggests that lipid metabolism in PDAC is better understood as a dynamic, interconnected adaptive network rather than a set of isolated metabolic pathways. This perspective supports biomarker-guided combination strategies that target context-dependent lipid dependencies and treatment-induced metabolic adaptation, rather than relying on inhibition of a single pathway.
SN  - 2234-943X
ER  -