The research team, led by Professor Wang Weiping (left), has pioneered a new cancer- treatment strategy that amplifies cancer cell starvation for amino acids, which blocks cancer nutrient scavenging and thus advancing precise starvation therapy.
Researchers at the LKS Faculty of Medicine, the University of Hong Kong (HKUMed), have pioneered a new cancer-treatment strategy that amplifies cancer cell starvation for amino acids. The study found that cancer cells can survive in nutrient-deprived environments by internalising extracellular proteins via macropinocytosis and degrading them through the proteasomal pathway. Leveraging this discovery, the HKUMed researchers engineered pH-responsive polymeric nanoparticles that release drugs to block both protein uptake and degradation, effectively achieving tumour starvation therapy. The research findings were published in Advanced Science [link to publication], and a US patent application has been filed.
Background
According to Hong Kong Cancer Statistics of 2022 from Hong Kong Cancer Registry, lung cancer remains the most prevalent malignancy, accounting for 16.1% of all new cancer cases in Hong Kong. Tumours with poor blood supply often exhibit nutrient-deficient microenvironments, lacking critical resources like amino acids and glucose. Previous studies indicated that cancer cells can scavenge extracellular proteins for survival through the lysosomal pathway, providing a source of amino acids for the cancer cells. However, whether other protein degradation systems also play a role in the utilisation of extracellular nutrients remained unclear.
Research method and results
The research team identified the macropinocytosis-proteasome pathway as a compensatory system for extracellular protein metabolism in cancer cells. Under amino acid starvation, cancer cells activated macropinocytosis to engulf extracellular proteins and degraded them via proteasomes. To disrupt this process, the research team developed pH-responsive nanoparticles for the co-delivery of macropinocytosis inhibitors and proteasome inhibitors.
In an experiment, the nanoparticles were injected into a lung tumour-bearing mouse model. The research team found that the nanoparticles effectively released drugs to simultaneously inhibit protein internalisation and proteasomal degradation in acidic tumour microenvironments, achieving synergistic tumour starvation.
Significance of the research
Professor Wang Weiping, Associate Professor in the Department of Pharmacology and Pharmacy and the Dr Li Dak-Sum Research Centre at HKUMed, and Principal Investigator of the State Key Laboratory of Pharmaceutical Biotechnology, said, 'Our work has uncovered the macropinocytosis-proteasome axis as another critical nutrient supply route for extracellular protein uptake and degradation—distinct from the classical lysosomal degradation pathway. This finding reveals the macropinocytosis-proteasome system as a novel therapeutic target for starvation therapy.'
To expedite the clinical translation of this strategy, the research team developed novel pH-responsive polymeric nanoparticles that suppress the amino acid level in cancer cells, thereby achieving therapeutic tumour starvation. He added, 'Our pH-responsive nanoparticles offer a new strategy for blocking cancer nutrient scavenging, thus advancing precise starvation therapy.'
About the research team
The study was led by Professor Wang Weiping, Associate Professor in the Department of Pharmacology and Pharmacy, and the Dr Li Dak-Sum Research Centre at HKUMed, and a Principal Investigator at the State Key Laboratory of Pharmaceutical Biotechnology. The co-first authors of the study were Dr Wang Tianyi, PhD graduate, and Dr Zhang Yaming, Postdoctoral fellow, from the same department.
Acknowledgements
This work was supported by the National Natural Science Foundation of China (Excellent Young Scientist Fund).
