A potent nano-strategy for dual energy deprivation to inhibit pancreatic cancer progression

Pancreatic cancer is a highly malignant tumor that poses significant threats to public health, and glycolysis plays a crucial role in its energy metabolism. Here, glycolysis was confirmed to be directly associated with poor prognosis through the use of clinical samples from 130 patients with pancreatic ductal adenocarcinoma (PDAC), and the effectiveness of zinc ions (Zn²⁺) in inhibiting glycolysis-related genes was further validated. Therefore, polyvinyl pyrrolidone (PVP)-modified zinc sulfide nanomedicines (ZnS-PVP) were developed for dual energy suppression by targeting glycolysis and mitochondrial respiration in pancreatic cancer. On the one hand, the released Zn²⁺ efficiently inhibited glycolysis in pancreatic cancer cells through the PI3K-Akt-mTOR-HIF-1α signaling axis. On the other hand, acid-responsive release of hydrogen sulfide (H₂S) gas damaged mitochondria and further reduced energy compensation by inhibiting oxidative phosphorylation. This two-pronged energy deprivation nano-strategy effectively eliminated pancreatic cancer cells and was proven to overcome chemotherapeutic resistance. Moreover, ZnS-PVP administration combined with immune checkpoint blockade (ICB) therapy significantly suppressed tumor progression in mouse orthotopic pancreatic tumor models, as also demonstrated in a pancreatic cancer patient-derived xenograft (PDX) model. Our work highlights the positive role of bioactive metal ions in targeting tumor energy metabolism and the great potential of nano-strategy for energy deprivation in the treatment of pancreatic cancer.