Neuroblastoma is the most common solid tumor found outside the brain in children and accounts for nearly 10% of all childhood cancer diagnoses, while causing almost 15% of deaths from childhood cancers. Despite the use of very aggressive and toxic combination treatments, children with high-risk neuroblastoma still have poor survival rates, and there are currently no cures for children whose disease comes back after treatment. High-risk neuroblastoma includes several genetic subtypes. Among these, the most deadly forms are those with changes in a gene called ATRX, which normally helps control how DNA is organized in cells. ATRX mutant neuroblastomas are especially aggressive compared with other high-risk types. This is partly because current standard immunotherapy treatments are less effective against them, and these tumors are also resistant to standard chemotherapy drugs. Identifying new immunotherapeutic targets that these tumors can not escape immune-based treatments and how they develop resistance to chemotherapy—leading to relapse and death—are poorly studied. Answering these two critical questions is the main focus of the proposed research.