Researchers are making progress in the fight against neuroblastoma (NB), a challenging childhood tumour known for its resistance to chemotherapy. A new study highlights ferroptosis, a form of iron-dependent cell death, as a crucial vulnerability in NB cells. Notably, the authors reveal that refractory NB shows increased antioxidant pathway activity, allowing it to tolerate harsh treatments. However, ferroptosis can be triggered through several distinct mechanisms, both in cell cultures and animal models.
Crucially, the team discovered standard chemotherapy can interfere with some types of ferroptosis induction, particularly those that act by targeting the antioxidant enzyme GPX4. This complex interplay means that drug combinations must be chosen wisely: simply adding a ferroptosis-inducing agent is not always effective.
The real breakthrough came with the combination of chemotherapy and Auranofin, a drug that blocks thioredoxin reductase. This duo worked better than chemotherapy alone, even in tumours that were previously resistant to treatment. In a patient-derived xenograft model of chemoresistant NB, survival improved and the proportion of aggressive, immature NB cells fell sharply. Researchers found that this drug combination acts by promoting ferritin degradation (“ferritinophagy”), lysosome accumulation, and dangerous iron overload—all hallmarks of ferroptosis.
The study concludes that, if chosen based on a clear understanding of how each agent acts, incorporating ferroptosis-inducing drugs alongside standard clinical treatment is both feasible and potentially more effective in high-risk NB. The findings open a door to improved protocols and better outcomes for children facing this aggressive cancer.
Reference
Mañas A et al. Targeted ferroptosis induction enhances chemotherapy efficacy in chemoresistant neuroblastoma. NPJ Precis Oncol. 2025;9(1):311.
