Spatial Multiomics Analyses Reveal That Diabetes Promotes Pancreatic Cancer Progression by Stimulating Cholesterol-Induced Neutrophil Extracellular Trap Formation

Patients with pancreatic ductal adenocarcinoma (PDAC) with diabetes mellitus (DM) exhibit poor clinical outcomes. Metabolic reprogramming of both cancer cells and immune compartments plays a crucial role in shaping the antitumor immune response in PDAC. DM-induced metabolic alteration may disrupt the intricate cross-talk between immune cells and tumor-associated immune factors, profoundly influencing PDAC progression. In this study, we performed an integrated, spatially resolved multiomics study to investigate DM-associated, cell-specific metabolic remodeling within the PDAC tumor microenvironment. DM influenced interactions between tumor cells and immune cells, which accelerated PDAC growth in both humans and mice. Patients with PDAC with DM exhibited higher tumor stage, poorer differentiation, and worse outcomes. Spatial metabolic and transcriptional profiling revealed that SREBP2-dependent cholesterol biosynthesis exacerbated PDAC progression. Increased cholesterol biosynthesis promoted neutrophil recruitment and accelerated the formation of neutrophil extracellular traps (NET) by stimulating the CXCL1/CXCR1/CXCR2 signaling axis, ultimately promoting PDAC growth. Inhibition of SREBP2, pharmacologic blockade of CXCL1, or perturbation of NETs markedly reduced PDAC growth in diabetic mouse models. Together, these multiomics analyses and follow-up mechanistic studies constitute an integrated approach that elucidates a metabolic mechanism by which diabetes promotes PDAC development by remodeling the tumor-immune microenvironment and highlights a potential therapeutic strategy for PDAC with DM. SIGNIFICANCE: Diabetes induces metabolic reprogramming that promotes neutrophil recruitment and neutrophil extracellular trap formation to drive pancreatic cancer progression, providing a targetable metabolism-immune axis to improve the outcomes of diabetic pancreatic cancer patients.