Targeting macropinocytosis for cancer therapy.

Macropinocytosis is a nutrient-scavenging process that enables cells to engulf large volumes of extracellular fluid and solutes through dynamic plasma membrane ruffling. In cancer, this evolutionarily conserved process is frequently hijacked to meet the heightened metabolic demands of malignant cells, particularly under conditions of nutrient deprivation. Through macropinocytosis, tumour cells internalize diverse extracellular components - including proteins, nucleotides, lipids, ions and debris from dead cells - which are subsequently degraded in lysosomes and recycled to support biosynthesis and energy production. This process is tightly regulated by oncogenic signalling pathways and cues from the tumour microenvironment, including those associated with oncogene activation, loss of tumour suppressors and hypoxia. Beyond facilitating tumour growth and metabolic adaptation, macropinocytosis is implicated in resistance to chemotherapy, radiotherapy, targeted therapy and immunotherapy. When excessively activated, it can also lead to methuosis, a form of non-apoptotic cell death characterized by macropinosome overload. This Review outlines the molecular mechanisms and functional consequences of macropinocytosis in cancer, highlighting its dual potential as a metabolic vulnerability and a route for therapeutic delivery. Continued investigation into its regulation, context-specific roles and pharmacological modulation may uncover new opportunities for combination therapies and precision cancer treatment.