Abstract A063: Lipid metabolism-driven remodeling of immune ecosystem promotes pancreatic cancer progression and metastasis

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a devastating malignancy characterized by aggressive metastatic progression, profound immunosuppression, and limited therapeutic options. Increasing evidence suggests that metabolic reprogramming extends beyond fuel provision and actively reshapes the tumor microenvironment (TME) to promote immune evasion and metastatic dissemination. However, the molecular mechanisms linking lipid metabolism to oncogenic signaling and remodeling of immune ecosystem remain poorly understood. Our preliminary studies identify Fatty Acid Synthase (FASN) as a non-canonical signaling hub that orchestrates immune exclusion and metastatic progression in PDAC. We uncovered a novel biochemical pathway in which FASN promotes site-specific palmitoylation of Myc, thereby enhancing c-Myc oncogenic activity. This signaling axis sustains oncogenic transcriptional programs, recruits immunosuppressive myeloid populations, and promotes CD8+ T-cell dysfunction, ultimately establishing a permissive metastatic niche. To translate these findings into therapeutic opportunities, we investigated the molecular mechanisms regulating c-Myc palmitoylation in PDAC and determined how palmitoyl transferase (ZDHHC) mediated palmitoylation controls oncogenic signaling. Using multiplex immunofluorescence (mIF), we mapped the spatial immune ecosystem of metastatic PDAC and characterized interactions between FASN-high tumor cells, macrophage populations, and dysfunctional CD8+ T cells within metastatic niches. Furthermore, leveraging our unique KPFFC (FASN conditional knockout) mouse model together with the clinical-stage FASN inhibitor, denifanstat, we evaluated whether disrupting the FASN–ZDHHC–c-Myc signaling axis can remodel the TME, restore antitumor immunity, and enhance sensitivity to immune checkpoint blockade. By shifting the focus of FASN biology from metabolic fuel production to its functional oncogenic signaling architecture, this study uncovers a therapeutically actionable immunometabolic vulnerability and establishes a mechanistic foundation for precision-guided immunometabolic therapies in pancreatic cancer.