The Emerging Role of Ferroptosis in Pediatric Cancer Biology and Therapy

Ferroptosis is a regulated form of cell death caused by iron-dependent membrane lipid peroxidation. Iron metabolism, membrane lipid composition, cellular metabolic pathways, and antioxidant defense systems regulate ferroptosis. Recently, ferroptosis has attracted interest as a target in cancer therapy, in particular cancer cells have developed several biological adaptative mechanisms to evade ferroptosis, thus enhancing tumor progression, metastatic dissemination, stemness, and resistance to conventional therapies. Interestingly, ferroptosis is regulated by the tumor microenvironment, where hypoxia, immune cells, and stromal components can either stimulate or inhibit ferroptotic cell death. It has been demonstrated that targeting ferroptosis, alone or in combination with chemotherapy, radiotherapy and immunotherapy, has anticancer effects in preclinical models and may contribute to avoid treatment resistance. However, the role of ferroptosis in pediatric cancer remains incompletely understood since these kinds of tumors show different developmental, genomic, and metabolic features that may contribute to create different ferroptosis vulnerabilities. Emerging evidence in neuroblastoma, B-cell acute lymphoblastic leukemia, osteosarcoma, and medulloblastoma supports the involvement of ferroptosis-related pathways in tumor biology and treatment response. Preclinical studies also indicate that ferroptosis induction may represent a therapeutic strategy in selected pediatric cancer models, although tumor heterogeneity, drug delivery, and potential toxicity to developing tissues remain important translational challenges. This review summarizes the molecular mechanisms underlining the relationship between ferroptosis and cancer biology, tumor progression, tumor microenvironment, and therapy resistance, with particular interest in its emerging relevance and therapeutic potential in pediatric oncology, while critically considering the current evidence and major challenges for clinical translation.