Targeting GLUTs in Cancer: Mechanisms, Combination Strategies, and Translational Challenges

Cancer cells exhibit metabolic reprogramming, most notably the Warburg effect, which underscores their heightened dependency on glucose uptake facilitated by glucose transporters (GLUTs). While targeting GLUTs holds promise for disrupting tumor metabolism, monotherapeutic inhibition often leads to compensatory resistance mechanisms, metabolic plasticity, and dose-limiting toxicity. This review comprehensively examines the rationale and mechanisms underlying combined strategies that integrate GLUT inhibitors with conventional chemotherapy, targeted therapy, immunotherapy, and radiotherapy. Such combinations exploit synthetic lethality, reverse immunosuppression, enhance DNA damage, and overcome adaptive resistance. We also discuss emerging approaches such as isoform-specific inhibitors, nanocarrier-based delivery, and artificial intelligence-guided combination design to improve selectivity and efficacy. Finally, we highlight key translational challenges and discuss how cross-disease insights into GLUT biology may inform the safety, selectivity, and therapeutic design of cancer-directed GLUT-targeted combination strategies.