Amino Acid‐Starved Cancer Cells Utilize Macropinocytosis and Ubiquitin‐Proteasome System for Nutrient Acquisition

Abstract To grow in nutrient‐deprived tumor microenvironment, cancer cells often internalize and degrade extracellular proteins to refuel intracellular amino acids. However, the nutrient acquisition routes reported by previous studies are mainly restricted in autophagy‐lysosomal pathway. It remains largely unknown if other protein degradation systems also contribute to the utilization of extracellular nutrients. Herein, it is demonstrated that under amino acid starvation, extracellular protein internalization through macropinocytosis and protein degradation through ubiquitin‐proteasome system are activated as a nutrient supply route, sensitizing cancer cells to proteasome inhibition. By inhibiting both macropinocytosis and ubiquitin‐proteasome system, an innovative approach to intensify amino acid starvation for cancer therapy is presented. To maximize therapeutic efficacy and minimize systemic side effects, a pH‐responsive polymersome nanocarrier is developed to deliver therapeutic agents specifically to tumor tissues. This nanoparticle system provides an approach to exacerbate amino acid starvation for cancer therapy, which represents a promising strategy for cancer treatment.