Acute lymphoblastic leukemia (ALL) is the most common pediatric malignancy, characterized by the clonal proliferation of immature lymphoid precursors. The distinction between B-cell ALL (B-ALL) and T-cell ALL (T-ALL) is fundamental, as each subtype exhibits distinct cytomorphological, genetic, and clinical features influencing prognosis and therapeutic strategies. Conventional multi-phase chemotherapy has significantly improved survival rates, yet its efficacy is limited by severe short- and long-term toxicities, highlighting the need for more selective therapeutic approaches. Advances in molecular profiling have enabled the identification of key oncogenic pathways, paving the way for targeted therapies such as tyrosine kinase inhibitors (TKIs), JAK-STAT pathway inhibitors, BCL-2 antagonists, and agents modulating epigenetic and cell cycle regulators. Concurrently, immunotherapeutic strategies have transformed the therapeutic landscape of pediatric ALL. Bispecific antibodies such as blinatumomab (anti-CD19), antibody–drug conjugates like inotuzumab ozogamicin (anti-CD22), and monoclonal antibodies such as daratumumab (anti-CD38) have demonstrated efficacy in relapsed or refractory disease with improved safety profiles. Moreover, CAR-T-cell therapy, particularly CD19-directed products, has shown unprecedented remission rates in refractory B-ALL. The integration of targeted and immune-based therapies into conventional regimens represents a decisive step toward precision medicine, aiming to enhance survival outcomes while reducing treatment-related toxicity and improving quality of life in ALL children. This review aims to provide a comprehensive overview of the current understanding of ALL pathobiology and therapeutic approaches, with particular emphasis on the expanding role of immunotherapeutic strategies in pediatric disease.

Immune thrombocytopenia (ITP) is the most common pediatric thrombocytopenia, characterized by immune-mediated platelet destruction and altered inflammatory responses. Among these alterations, mesenchymal stromal cells (MSCs) from ITP patients display reduced viability and impaired immunoregulatory functions. Our previous work revealed dysregulated iron metabolism in ITP-MSCs, with increased intracellular iron accumulation driven by hepcidin–FPN1 axis disruption and overexpression of iron importers. Given the link between iron overload, oxidative stress, and ferroptosis, a regulated iron-dependent form of cell death, we investigated whether ITP-MSCs exhibit oxidative and molecular alterations associated with ferroptosis. ITP-MSCs showed increased ROS levels and ACSL4 expression, together with reduced expression of proteins involved in ferroptosis-related antioxidant defense, including SLC3A2, SLC7A11, and GPX4. Increased extracellular release of HMGB1, a DAMP associated with cellular stress and different forms of regulated cell death, was also observed. Treatment with Ferrostatin-1 (Fer-1) and Deferasirox (DFX) reduced oxidative stress and partially restored the expression of ferroptosis-related markers. Similarly, high-dose dexamethasone (HD-Dexa) reduced ROS and ACSL4 levels and limited extracellular HMGB1 release. Collectively, these findings support increased susceptibility to ferroptotic stress in ITP-MSCs and reveal a ferroptosis-associated oxidative stress phenotype with concomitant alterations in ferroptosis-related molecular pathways. Moreover, the effects of HD-Dexa, DFX, and Fer-1 suggest that modulation of these pathways may represent a potential strategy for limiting oxidative cellular damage in ITP-MSCs.

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.

OS is the most common primary malignant bone tumor, predominantly affecting children, adolescents, and young adults. Despite advances in multimodal treatment, patient outcomes have remained largely unchanged over the past decades, particularly in cases of metastatic or recurrent disease. Increasing evidence highlights the pivotal role of the tumor microenvironment (TME) in OS progression, metastasis, immune evasion, and therapeutic resistance. The OS TME comprises a complex and dynamic network of tumor cells, immune cells, cancer-associated fibroblasts, mesenchymal stromal cells, endothelial cells, extracellular matrix components, and soluble factors that collectively regulate tumor behavior. This review summarizes the current understanding of the OS TME, highlighting the interactions between malignant cells and their surrounding microenvironment and their contribution to tumor growth, angiogenesis, invasion, metastatic dissemination, and treatment response. Moreover, here we discuss the strengths and limitations of the most relevant preclinical models currently used to investigate OS biology and evaluate novel therapeutic strategies. Three-dimensional (3D) culture systems, including spheroids, organoids, and biomimetic scaffold-based models, today are considered the models able to best recapitulate the structural, mechanical, and cellular complexity of the native tumor microenvironment than conventional two-dimensional cultures. In addition, patient-derived xenograft (PDX) models are reviewed for their ability to preserve the histopathological, molecular, and genetic characteristics of the original tumors, making them valuable platforms for translational research, biomarker discovery, and personalized medicine.