Nanomedicine strategies for overcoming cellular and microenvironmental barriers to cuproptosis-based cancer therapy.

Cuproptosis, a copper-dependent form of regulated cell death driven by mitochondrial proteotoxic stress, has emerged as a promising vulnerability for cancer therapy. However, its therapeutic translation is limited by cellular and microenvironmental barriers that restrict effective copper delivery, intracellular copper accumulation, mitochondrial engagement, and antitumor immune activation. This review summarizes the molecular basis of cuproptosis, including copper homeostasis, mitochondrial copper trafficking, lipoylated protein aggregation, and iron‑sulfur cluster disruption. We then examine how dysregulated copper transport, glutathione-mediated buffering, metabolic reprogramming, hypoxia, and immunosuppressive tumor microenvironments attenuate cuproptosis-based treatment. Focusing on these barriers, we discuss nanomedicine strategies designed to modulate copper homeostasis, deplete glutathione, reprogram tumor metabolism, alleviate hypoxia, and enhance antitumor immunity. These multifunctional platforms can enable tumor-selective copper delivery and spatiotemporally controlled activation while integrating complementary therapeutic modalities. Finally, we highlight unresolved challenges, including incomplete mechanistic understanding, tumor heterogeneity, insufficient real-time monitoring of cuproptosis, and the need to balance therapeutic efficacy with systemic copper toxicity. A systems-level integration of nanomedicine, mechanistic biology, and computational design may support the development of safer, more precise, and clinically actionable cuproptosis-based cancer therapies.