Diet-induced macrophage-driven inflammation fuels pancreatic plasticity and aggressiveness

High-fat diet (HFD) and obesity are increasingly recognized as risk factors of pancreatic ductal adenocarcinoma (PDAC), yet the mechanisms by which dietary fat contribute to oncogenic transformation remain elusive. Using an inducible acinar-specific KrasG12V/Trp53-loss genetically-engineered mouse model of PDAC, we established early-and late-onset protocols to assess age-dependent susceptibility to HFD. Specifically, HFD accelerated tumorigenesis with poorer prognosis in early-onset mice and, strikingly, enabled full PDAC development in late-onset adult mice otherwise resistant to oncogenic transformation. Tumors arising under HFD activated a distinct transcriptional and epigenetic state enriched in pathways or genes related to stemness, plasticity, and metastatic competence, which was maintained even in tumor-derived cell lines. Mechanistically, fatty acid-educated macrophages secreted the cathelicidin antimicrobial peptide (CAMP), activating P2X purinoceptor 7 (P2RX7) signaling in tumor cells to drive a highly plastic, immune-evasive phenotype reinforced by the expression of the peptidoglycan recognition protein 1 (PGLYRP1), further shielding tumor cells from macrophage phagocytosis. Functionally, HFD-induced tumors displayed enhanced metastatic potential independent of host context. Analysis of 164 human PDAC samples revealed that elevated body-mass index (BMI) was associated to a conserved CAMP-P2RX7-CXCR4 signature, maintained despite weight loss during disease progression. Together, these findings uncover a diet-imprinted macrophage-tumor cell circuit that promotes transformation and accelerates PDAC progression, positioning it as a therapeutic vulnerability in obesity-associated pancreatic cancer. Statement of significanceHigh-fat diet induces pancreatic tumorigenesis in adult tissue, driving metastatic competence and a plastic state, and ultimately engages a macrophage-derived CAMP-P2RX7 circuit that reinforces immune evasion and accelerates PDAC progression.