Macropinocytosis: Both a Target and a Tool for Cancer Therapy

Macropinocytosis is a non-selective, clathrin-independent endocytic process that facilitates bulk internalization of extracellular fluid and its dissolved components (including proteins, lipids, and nucleotides) through plasma membrane remodeling and the subsequent formation of macropinosomes. This evolutionarily conserved cellular process plays important roles in nutrient supply, immune response, and metabolism. Particularly, cancer cells exploit activated macropinocytosis to obtain nutrients for supporting proliferation and survival under nutritional stress. Thus, macropinocytosis emerges as an important target for cancer therapy. Furthermore, as activated macropinocytosis constitutively uptakes extracellular fluids into cancer cells, it has been utilized for delivering anti-tumor drugs in cancer therapy. In this review, we systematically addressed progress in cancer therapeutic strategies in both targeting macropinocytosis and utilizing macropinocytosis as an anti-cancer drug delivering tool, including therapeutic applications with macropinocytosis inhibitors; metabolic modulators; methuosis (the macropinocytosis-associated cell death) inducers; and macropinocytosis-mediated anti-cancer drug delivery strategies such as nanoparticles, viral vectors, extracellular vesicles, and targeted conjugates. We conclude that developing targeted macropinocytosis anti-cancer drugs and exploring macropinocytosis-dependent anti-cancer drug delivery systems open new avenues for cancer therapy.