From Traditional Therapies to Nanomedicine: A Thorough Examination of Atypical Teratoid Rhabdoid Tumor Treatment...

Atypical teratoid/rhabdoid tumor (ATRT) is a rare but highly aggressive pediatric central nervous system malignancy characterized by SMARCB1 or SMARCA4 loss, leading to profound epigenetic dysregulation. Despite multimodal treatment incorporating surgery, chemotherapy, radiotherapy, and intrathecal therapy, long-term survival remains poor due to tumor recurrence, resistance, and treatment-related toxicities in young children. Molecular profiling has defined three subgroups: ATRT-MYC, ATRT-SHH, and ATRT-TYR highlight biological heterogeneity and the need for subgroup-specific strategies. Emerging targeted and combinational therapies, including Aurora A kinase inhibitors, IGF-1R blockers, enhancer of zeste homologue 2 (EHZ2) and histone deacetylase (HDAC) inhibitors, retinoids, intrathecal regimens, and radio-enhancers, are broadening therapeutic options, and immunotherapy represents an additional avenue for exploration. Nanomedicine provides a promising platform for overcoming the blood-brain barrier, enabling tumor-specific delivery, and integrating genetic and epigenetic interventions. Preclinical studies have demonstrated the potential of nanoparticles to restore SMARCB1 expression, inhibit epigenetic drivers, and deliver multifunctional therapeutic payloads tailored to subgroup vulnerabilities. Nonetheless, translational barriers such as delivery efficiency, scalability, pediatric safety, and regulatory challenges must be addressed before these strategies reach clinical practice. This review integrates insights into ATRT biology, conventional management, and emerging molecular-, immunological-, and nanotechnology-based approaches, emphasizing opportunities and challenges in advancing outcomes for children affected by this devastating tumor.