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This review gives a systematically investigation of how metabolic reprogramming contributes to drug resistance in cancer, including aerobic glycolysis (also known as the Warburg effect), lactate metabolism, glutamine addiction, lipid synthesis reprogramming, mitochondrial and ion metabolic changes. Furthermore, by clarifying the mechanisms behind these reprogrammed metabolic pathways, we explain how these changes lead to drug resistance and highlight potential molecular targets for therapeutic intervention. Additionally, we discuss emerging strategies aimed at exploiting these metabolic vulnerabilities, offering new insights for overcoming drug resistance in cancer. By integrating recent discoveries in this field, we present a unified perspective on targeting metabolic vulnerabilities to overcome drug resistance, which is an urgent need in precision oncology, and timely and concise insights for cancer biologists and researchers in the field of exploring the metabolic mechanisms of drug resistance. We hope this review will provide valuable insights for molecular tumor biologists seeking to elucidate the molecular roles of tumor metabolic reprogramming and drug resistance in cancer.<\/jats:p>","DOI":"10.7717\/peerj.21400","type":"journal-article","created":{"date-parts":[[2026,6,8]],"date-time":"2026-06-08T08:57:15Z","timestamp":1780909035000},"page":"e21400","source":"Crossref","is-referenced-by-count":0,"title":["The metabolic escape: how tumor metabolic reprogramming drives drug resistance"],"prefix":"10.7717","volume":"14","author":[{"given":"Yan","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Laboratory Medicine, Peking University First Hospital, Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zixu","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, Peking University First Hospital, Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenzhe","family":"Si","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University Third Hospital, Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xujun","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, Peking University First Hospital, Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"4443","published-online":{"date-parts":[[2026,6,8]]},"reference":[{"key":"10.7717\/peerj.21400\/ref-1","doi-asserted-by":"publisher","first-page":"5810","DOI":"10.3390\/cancers13225810","article-title":"Metabolic plasticity in melanoma progression and response to oncogene targeted 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