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However, the nutrient acquisition routes reported by previous studies are mainly restricted in autophagy\u2010lysosomal 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\u2010proteasome system are activated as a nutrient supply route, sensitizing cancer cells to proteasome inhibition. By inhibiting both macropinocytosis and ubiquitin\u2010proteasome 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\u2010responsive 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.<\/jats:p>","DOI":"10.1002\/advs.202304791","type":"journal-article","created":{"date-parts":[[2023,11,21]],"date-time":"2023-11-21T04:21:54Z","timestamp":1700540514000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Amino Acid\u2010Starved Cancer Cells Utilize Macropinocytosis and Ubiquitin\u2010Proteasome System for Nutrient Acquisition"],"prefix":"10.1002","volume":"11","author":[{"given":"Tianyi","family":"Wang","sequence":"first","affiliation":[{"name":"State Key Laboratory of Pharmaceutical Biotechnology The University of Hong Kong  Hong Kong China"},{"name":"Department of Pharmacology and Pharmacy Li Ka Shing Faculty of Medicine The University of Hong Kong  Hong Kong China"},{"name":"Dr. Li Dak\u2010Sum Research Centre The University of Hong Kong  Hong Kong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaming","family":"Zhang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Pharmaceutical Biotechnology The University of Hong Kong  Hong Kong China"},{"name":"Department of Pharmacology and Pharmacy Li Ka Shing Faculty of Medicine The University of Hong Kong  Hong Kong China"},{"name":"Dr. Li Dak\u2010Sum Research Centre The University of Hong Kong  Hong Kong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuwei","family":"Liu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Pharmaceutical Biotechnology The University of Hong Kong  Hong Kong China"},{"name":"Department of Pharmacology and Pharmacy Li Ka Shing Faculty of Medicine The University of Hong Kong  Hong Kong China"},{"name":"Dr. Li Dak\u2010Sum Research Centre The University of Hong Kong  Hong Kong 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