IL-37 links ACLY-centered lipid metabolic reprogramming to myeloid immunosuppression in pancreatic ductal adenocarcinoma

This study investigated the role of IL-37 in PDAC and its association with lipid metabolic reprogramming and tumour immune suppression. Bioinformatic analyses, paired clinical specimens, IL-37 gain- and loss-of-function models, and in vitro and in vivo functional assays were used to characterize the role of IL-37 in PDAC. Tumour immune profiles and metabolic alterations were assessed by flow cytometry, immunofluorescence, molecular analyses, and untargeted metabolomics. Bone marrow-derived MDSC assays and pharmacological AKT inhibition were used for mechanistic validation, and the effects of ACLY inhibition and Gr-1 blockade were further evaluated in vivo. IL-37 was upregulated in PDAC tissues and cell lines and was associated with shorter overall survival. IL-37 overexpression enhanced cell viability, clonogenicity, migration, invasion, and tumour growth, whereas IL-37 knockdown produced the opposite effects. IL-37 overexpression was also associated with increased CD11b + Gr-1 + myeloid-derived suppressor cell accumulation and impaired CD8 + T-cell infiltration. Tumour-derived IL-37-associated signals further promoted MDSC generation and preferentially shifted the population toward M-MDSCs in vitro. Metabolomic and molecular analyses revealed an ACLY-centred lipid metabolic programme involving increased ACLY, FASN, and SPHK1 expression and alterations in acetyl-CoA, palmitate, and sphingosine-1-phosphate. IL-37 enhanced AKT phosphorylation, whereas AKT inhibition attenuated the upregulation of ACLY, FASN, and SPHK1, supporting a functional role for AKT signalling in this metabolic phenotype. ACLY inhibition, particularly in combination with Gr-1 blockade, reduced lipid accumulation and myeloid-cell infiltration, restored CD8 + T-cell responses, and suppressed tumour growth. IL-37 promotes PDAC progression in association with AKT-related signalling, ACLY-centred lipid metabolic reprogramming and an immunosuppressive tumour microenvironment. Combined targeting of lipid metabolism and immunosuppressive myeloid cells may represent a therapeutic strategy for IL-37-high PDAC.