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.

Abstract

Pancreatic ductal adenocarcinoma (PDAC) frequently invades adjacent peripancreatic adipose tissue, yet the role of tumour-infiltrating adipocytes (TIAs) in shaping antitumour immunity remains unclear. To determine how TIAs influence PDAC progression and to define the immunometabolic mechanism involved. 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. 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. 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.