Tumor Lipidomic Changes after Treatment with Polymeric Hydroxychloroquine in a Syngeneic Murine Model of Pancreatic Cancer

Pancreatic Ductal Adenocarcinoma (PDAC) is one of the most lethal malignancies, with limited treatment options. Altered lipid metabolism, including dysregulated eicosanoid pathways, plays a role in PDAC progression and therapy resistance. In this study, we investigated the impact of a treatment with polymeric hydroxychloroquine (PCQ), a novel macromolecular derivative of hydroxychloroquine (HCQ), on tumor lipid metabolism in a syngeneic mouse model of PDAC. Using a validated LC-MS/MS method, we quantified 72 eicosanoids in tumors to assess the metabolic changes induced by PCQ and HCQ treatment. Our findings revealed significant PCQ-mediated downregulation of multiple protumorigenic eicosanoids, including PGD2, PGJ2, LTE4, LTB4, and HETEs, and upregulation of antitumor resolvins. This was further confirmed by Partial Least Squares Discriminant Analysis (PLS-DA) and heatmap analysis. The parent compound HCQ showed minimal impact on eicosanoid concentrations in the tumors, with no significant alterations at 24-h and modulation of only six eicosanoids downregulated at 72-h post treatment. Overall, our data highlight a novel role of PCQ in modulating tumor lipid metabolism, suggesting a unique mechanism of action and its potential as an adjuvant agent in the therapy of PDAC.