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.

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.