Macropinocytosis in KRAS-Mutant Cancers: Biological Functions and Therapeutic Opportunities in Pancreatic Ductal Adenocarcinoma

Oncogenic mutations in KRAS are primary drivers of human malignancies, particularly in pancreatic, colorectal, and lung adenocarcinomas. Although allele-selective inhibitors have shown clinical activity in some settings, their applicability varies by KRAS allele and tumor type. An important metabolic adaptation observed in selected KRAS-mutant tumor models, particularly pancreatic ductal adenocarcinoma (PDAC), is increased macropinocytosis, a clathrin-independent endocytic process that enables the nonselective engulfment of extracellular fluids and their solutes to support tumor growth. Although this process is physiologically restricted in most quiescent cells, macropinocytosis enables extracellular protein scavenging in several KRAS-mutant tumor models, thereby supporting amino acid availability and metabolism under nutrient-limited conditions. Macropinocytosis-associated uptake of cholesterol and ATP has also been reported in selected breast/ovarian and A549 lung cancer models, respectively; however, lipid acquisition through this route has not been established in KRAS-mutant PDAC, and the dependence of ATP uptake on mutant KRAS remains unclear. Beyond nutrient acquisition, macropinocytosis can mitigate microenvironmental stress, contribute to cytoskeletal remodeling and invasive progression, and reduce treatment sensitivity in selected preclinical models, although these effects depend on tumor lineage, genetic background, and experimental conditions. These context-dependent adaptive functions make hyperactive macropinocytic flux a potential gateway for targeted intervention. Therapeutic strategies currently under investigation include inhibition of macropinocytic nutrient uptake, utilization of macropinocytosis for drug delivery, and induction of methuosis, a non-apoptotic death phenotype associated with extensive vacuolization. Most evidence remains preclinical. This review systematically elucidates the molecular mechanisms governing macropinocytosis, its pleiotropic roles in tumor survival and malignant progression, with emphasis on PDAC, and discusses the evidence and limitations relevant to therapeutic development.