Macropinocytosis: A central orchestrator in tumor development and therapeutic resistance

Macropinocytosis, a dysregulated endocytic pathway prevalent in cancers, drives tumor progression by scavenging extracellular nutrients and activating oncogenic signaling. This review proposed a functional categorization of macropinocytosis based on the basal activity and stimulus origin. We then delineated the specific signaling networks governing this process and its cell type-specific functions within the tumor microenvironment, which collectively fuel malignant phenotypes and modulate diverse cell death modalities, including ferroptosis, cuproptosis, and alkaliptosis. Furthermore, we critically evaluated the therapeutic potential of targeting macropinocytosis in oncology, highlighting synergistic combination strategies and outlining key future directions such as the identification of specific biomarkers, exploration of non-canonical functions, and elucidation of its role in intercellular communication. This synthesis reframes macropinocytosis from a mere metabolic adaptation to a central orchestrator of tumor biology, thereby providing a robust rationale for its therapeutic inhibition in cancer.