Abstract
Pancreatic ductal adenocarcinoma (PDAC) grows within a highly fibrotic, pressurized microenvironment that collapses vasculature and restricts delivery of oxygen and circulating nutrients. To survive this metabolic stress, PDAC cells activate lysosome-centered nutrient acquisition and recycling programs, including macroautophagy, RAS-driven macropinocytosis, and receptor-mediated endocytosis, that traffic intracellular and extracellular cargo to lysosomes for degradation and metabolite export. These pathways are reinforced by oncogenic signaling and MiT/TFE-dependent lysosomal biogenesis, and they support core outputs of tumor metabolism such as iron bioavailability, amino acid and nucleotide pools, lipid homeostasis, and immune evasion. Lysosomal programs in nonmalignant compartments (fibroblasts, stellate cells, and immune cells) further shape nutrient exchange, matrix production, and whole-body metabolism, positioning the lysosome as a key node at the tumor–host interface. Although genetic and pharmacologic blockade of autophagy/lysosome function can produce potent antitumor effects in preclinical models, clinical trials with lysosomotropic agents have shown limited benefit, highlighting challenges in target engagement, biomarkers, and rational combination strategies. Here we review current tools and concepts for interrogating lysosomal flux in PDAC, integrate emerging insights from systemic metabolism and dietary interventions, and outline therapeutic opportunities for more effectively exploiting lysosome dependence in pancreatic cancer.