Tumour-infiltrating adipocyte-derived 12,13-DiHOME subverts CD8 + T cell immunity in pancreatic ductal adenocarcinoma by promoting PPARγ-mediated ferritinophagy and tumour-associated neutrophil ferroptosis

@article{luo2026tumourinfiltrating,
  title = {{Tumour-infiltrating adipocyte-derived 12,13-DiHOME subverts CD8 + T cell immunity in pancreatic ductal adenocarcinoma by promoting PPARγ-mediated ferritinophagy and tumour-associated neutrophil ferroptosis}},
  author = {Yan Luo and Jiayi Yang and Xinyuan Liu and Binru Zhang and Tianqi Yu and Jian Guan and Yiqin Song and Qiyuan Li and Tianqi Lu and Wei Liu and Linzhu Zou and Yongming Lin and Jiawen Wu and Yuncheng Han and Guanqun Li and Xinlei Yang and Yingmei Zhang and Hongtao Tan and X W Bai and Hua Chen and Jisheng Hu and Rui Kong and Bo Sun},
  journal = {Gut},
  year = {2026},
  month = may,
  doi = {10.1136/gutjnl-2025-337119},
  url = {https://doi.org/10.1136/gutjnl-2025-337119},
  note = {CC BY-NC},
}

TY  - JOUR
TI  - Tumour-infiltrating adipocyte-derived 12,13-DiHOME subverts CD8 + T cell immunity in pancreatic ductal adenocarcinoma by promoting PPARγ-mediated ferritinophagy and tumour-associated neutrophil ferroptosis
AU  - Yan Luo
AU  - Jiayi Yang
AU  - Xinyuan Liu
AU  - Binru Zhang
AU  - Tianqi Yu
AU  - Jian Guan
AU  - Yiqin Song
AU  - Qiyuan Li
AU  - Tianqi Lu
AU  - Wei Liu
AU  - Linzhu Zou
AU  - Yongming Lin
AU  - Jiawen Wu
AU  - Yuncheng Han
AU  - Guanqun Li
AU  - Xinlei Yang
AU  - Yingmei Zhang
AU  - Hongtao Tan
AU  - X W Bai
AU  - Hua Chen
AU  - Jisheng Hu
AU  - Rui Kong
AU  - Bo Sun
PY  - 2026
DA  - 2026/05/28
JO  - Gut
DO  - 10.1136/gutjnl-2025-337119
UR  - https://doi.org/10.1136/gutjnl-2025-337119
AB  - Background Pancreatic ductal adenocarcinoma (PDAC) frequently invades adjacent peripancreatic adipose tissue, yet the role of tumour-infiltrating adipocytes (TIAs) in shaping antitumour immunity remains unclear. Objective To determine how TIAs influence PDAC progression and to define the immunometabolic mechanism involved. Design We used orthotopic PDAC models and Kras(LSL-G12D/+);Trp53(LSL-R172H/+);Pdx1-Cre (KPC) mice, together with neutrophil lineage peroxisome proliferator-activated receptor gamma (PPARγ) conditional knockout mice (PPARγ(fl/fl)-S100A8(cre)). Tumour metabolomics, bulk RNA sequencing (bulk RNA-seq) and single-cell RNA sequencing (scRNA-seq) were integrated with adipocyte and tumour-associated neutrophil (TAN) co-culture assays. Human relevance was assessed in a retrospective PDAC cohort (n=121) and validated in public transcriptomic datasets. Results High TIA abundance correlated with poorer overall survival and an immune-suppressed tumour microenvironment (TME). In mouse models, adipocyte-enriched tumours showed reduced CD8 + T cell functions. Multiomics analyses highlighted the adipocyte-derived metabolite 12,13-dihydroxy-9Z-octadecenoic acid (12,13-DiHOME) and supported its role in increasing TAN ferroptosis susceptibility. Mechanistically, 12,13-DiHOME enhanced PPARγ-dependent ferritinophagy signalling in TANs, accompanied by increased ferroptosis and CXCL2 production. Genetic or pharmacologic disruption of this axis, CXCL2 neutralisation or CXCR2 blocking, attenuated tumour-promoting phenotypes and restored CD8 + T cell functions in vivo and in vitro. Conclusions These findings support an adipocyte-TAN immunometabolic circuit in PDAC, where TIA-derived 12,13-DiHOME promotes PPARγ-dependent TAN ferroptosis and increases CXCL2, leading to impaired CD8 + T cell functions. Targeting this pathway may help mitigate immune suppression in PDAC.
SN  - 0017-5749
SN  - 1468-3288
ER  -