Rewiring tumor metabolism for lethality: Nanomedicine-mediated induction of metabolic cell death

Metabolic cell death, a type of programmed cell death driven by metabolic imbalance, is a promising strategy to overcome tumor drug resistance and metabolic adaptability. Recent advances in ferroptosis, cuproptosis, and disulfidptosis have revealed their unique and interrelated roles in cancer, but single-agent approaches generally suffer from unsatisfactory therapeutic efficiency due to off-target toxicity, suboptimal efficacy, a tumor microenvironment (TME) heterogeneity. Although nanomedicine has been widely leveraged for therapeutic species delivery, its potential to induce metabolic cell death via precise targeting, controlled release, and synergistic mechanisms remains relatively understudied. This review describes the molecular pathways of these three notable types of metabolic cell death, summarizes state-of-the-art nano-delivery strategies, and highlights the progress in enhancing metabolic cell death through metabolic reprogramming and immune modulation. The crosstalk among these cell death modalities is discussed in detail, with an emphasis on the use of nano-combinatorial therapies to exploit their synergy. Finally, the existing challenges (mechanistic heterogeneity, biosafety, and clinical scalability) are proposed in conjunction with perspectives on next-generation nanomedicine to bridge preclinical and clinical gaps, providing new insights for clinical tumor treatment.