Neuroblastoma is a devastating pediatric cancer, with approximately 50% of diagnosed children experiencing recurrent disease despite aggressive multimodal treatments. Overcoming drug resistance represents a critical challenge in the management of this disease. Leveraging the power of single-cell genomics, we aim to deepen our understanding of neuroblastoma biology, particularly in elucidating complex processes that are not amenable to traditional bulk DNA/RNA sequencing methods, such as cancer cell clonal evolution and therapy resistance.\n\nIn this study, we conducted a comprehensive single-nuclei RNA sequencing (snRNA-seq) analysis, comparing matched PDX lines: the drug-sensitive COG-N-603x and its drug-resistant counterpart COG-N-623x, derived from the same patient before and after chemotherapy treatment.  Our overarching goal is to unveil distinct cellular states associated with drug resistance by juxtaposing the gene signatures of drug-sensitive and drug-resistant cells.