Zhu Yunhan, Yan Weijie, Tong Lingfeng, Yang Jie, Ge Shengfang, Fan Jiayan, Jia Renbing, Wen Xuyang
Department of Ophthalmology Ninth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine Shanghai China.
Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology Shanghai China.
MedComm (2020). 2025 Sep 6;6(9):e70358. doi: 10.1002/mco2.70358. eCollection 2025 Sep.
Cancer metabolic reprogramming is a fundamental hallmark that enables tumor cells to sustain their malignant behaviors. Beyond its role in supporting growth, invasion, and migration, metabolic rewiring actively contributes to anticancer drug resistance. Cancer cells not only reshape their own metabolism but also engage in aberrant metabolic crosstalk with nonmalignant components within the tumor microenvironment (TME). These metabolic alterations create multiple barriers to the efficacy of drug therapies, including chemotherapy, targeted therapy, and immunotherapy. Despite growing evidence, an integrated understanding of how metabolic reprogramming contributes to the development of drug resistance and how it may be therapeutically targeted to overcome the resistance remains incomplete. This review summarizes recent progresses in tumor-intrinsic and TME-associated metabolic alterations that contribute to drug resistance by sustaining metabolic needs and modulating nonmetabolic processes and explores the upstream regulatory mechanisms driving these changes, focusing particularly on glucose, lipid, and amino acid metabolism. We also discuss the current advances in the integration of small molecule inhibitors targeting cancer metabolism to address drug resistance. By consolidating mechanistic insights and therapeutic opportunities, this review highlights metabolic reprogramming as a promising intervention point to overcome anticancer drug resistance.
癌症代谢重编程是一种基本特征，它使肿瘤细胞能够维持其恶性行为。除了在支持生长、侵袭和迁移方面的作用外，代谢重塑还积极促成抗癌药物耐药性。癌细胞不仅重塑自身代谢，还与肿瘤微环境（TME）中的非恶性成分进行异常的代谢串扰。这些代谢改变为包括化疗、靶向治疗和免疫治疗在内的药物治疗疗效制造了多重障碍。尽管证据越来越多，但对于代谢重编程如何导致耐药性发展以及如何通过治疗靶向克服耐药性的综合理解仍不完整。本综述总结了肿瘤内在和TME相关代谢改变的最新进展，这些改变通过维持代谢需求和调节非代谢过程导致耐药性，并探讨了驱动这些变化 的上游调控机制，特别关注葡萄糖、脂质和氨基酸代谢。我们还讨论了整合靶向癌症代谢的小分子抑制剂以解决耐药性方面的当前进展。通过巩固机制见解和治疗机会，本综述强调代谢重编程是克服抗癌药物耐药性的一个有前景的干预点。
