Immunotherapeutic advances in pediatric neuroblastoma: Overcoming resistance through biomarker-guided combinations

Neuroblastoma is the most common extracranial solid tumor in children. It remains a major therapeutic challenge, particularly in high-risk cases where long-term survival rates remain below 50 % despite intensive multimodal treatment. The immunosuppressive tumor microenvironment (TME), marked by low MHC class I expression and infiltration of regulatory immune cells, has historically limited the efficacy of immune-based therapies. Recent advances in immunotherapy have reshaped the treatment landscape, with anti-GD2 monoclonal antibodies such as dinutuximab and naxitamab demonstrating significant clinical benefit, especially when combined with granulocyte-macrophage colony-stimulating factor (GM-CSF). Beyond antibody-based therapies, new modalities are advancing. CAR T-cell platforms targeting GD2, B7-H3, and L1CAM, along with checkpoint inhibitors, cytokine therapies, cancer vaccines, and oncolytic viruses, are showing early promise. However, resistance mechanisms, such as antigen loss, T-cell exhaustion, and suppressive myeloid populations, continue to hinder durable responses. Biomarkers such as Anaplastic Lymphoma Kinase (ALK) mutation status, immune infiltration profiles, and cytokine signatures are increasingly guiding patient stratification and therapeutic personalization. Combination strategies integrating immunotherapy with chemotherapy, radiotherapy, and targeted agents have demonstrated synergistic potential, and recent clinical trials reflect a shift toward multi-agent regimens. Novel platforms such as armored CARs, bispecific antibodies, and metabolic modulators are expanding the therapeutic horizon. This review synthesizes current evidence on immunotherapeutic strategies in neuroblastoma, highlighting resistance pathways, biomarker-driven approaches, and the evolving clinical trial landscape. Future directions emphasize personalized, biomarker-guided immunotherapy to improve efficacy, reduce toxicity, and establish durable, curative outcomes for children with neuroblastoma. • Anti-GD2 antibodies improve survival but cause neuropathic pain and AEs. • Resistance stems from GD2 loss, T-cell exhaustion, and suppressive myeloid cells. • Biomarkers (ALK, immune infiltration, cytokines) can guide patient selection. • Combination regimens with chemo, radiotherapy, and targeted agents show synergy. • Emerging CAR-T/NK, bispecific antibodies, and oncolytic viruses expand options.