<p>The glutathione (GSH) redox system plays a central role in maintaining cellular homeostasis, but its dysregulation in cancer contributes to tumor progression, therapy resistance, and metabolic adaptation. Elevated intracellular GSH levels represent both a barrier to conventional therapies and an opportunity to design redox-responsive drug delivery systems. In recent years, GSH has emerged as a promising therapeutic trigger and biomarker, driving the development of nanotechnology-enabled platforms for controlled drug release, imaging, and theranostics. This review provides a critical and translational analysis of GSH-responsive nanomedicine, highlighting chemical strategies such as disulfide/diselenide linkages, transition metal systems, and GSH-activated prodrugs. Unlike prior reviews, which often present descriptive overviews, this article emphasizes comparative evaluation of design principles, biological mechanisms, and translational hurdles, including biosafety, tumor heterogeneity, and large-scale manufacturability. We further outline future perspectives such as hybrid multifunctional nanoplatforms, patient-specific redox profiling, and clinical pathways for regulatory approval. By integrating insights from redox biology and nanotechnology, this review offers a timely and original perspective on the opportunities and challenges of exploiting tumor redox imbalance for precision drug delivery and cancer therapy.</p> Graphical Abstract <p></p>