GD2-targeted immunotherapy in pediatric bone sarcomas: a systematic review of emerging strategies and combination approaches.

Primary bone sarcomas, including Osteosarcoma (OS) and Ewing sarcoma (ES), are rare pediatric malignancies with limited therapeutic advances over recent decades and poor outcomes, especially for patients with metastatic and refractory/relapsed disease. Disialoganglioside 2 (GD2) has emerged as a promising immunotherapeutic target due to its high expression in pediatric bone sarcomas and its role in tumor progression and treatment resistance. This systematic review summarizes current evidence on GD2-targeted therapies and combination strategies in pediatric bone sarcomas. A systematic review was conducted according to PRISMA 2020 guidelines using PubMed, Embase, Web of Science, and ClinicalTrials.gov. Preclinical and clinical studies investigating GD2-targeted therapies in pediatric bone sarcomas were included, together with registered clinical trials. Twenty-six studies met inclusion criteria, including 17 preclinical and 9 clinical studies, alongside 15 ongoing clinical trials. Preclinical evidence consistently demonstrated antitumor activity of GD2-directed approaches, including monoclonal antibodies (mAbs), CAR-T cells, bispecific antibodies, and radio-immunotherapy. Combination strategies, particularly anti-GD2 mAbs with chemotherapy, enhanced antitumor efficacy through induction of apoptosis, activation of endoplasmic reticulum stress pathways, and inhibition of tumor invasiveness. Clinical evidence, although limited and heterogeneous, suggested encouraging activity of Dinutuximab beta-based chemo-immunotherapy, especially in ES. Several clinical trials are ongoing, mainly early-phase and focusing on relapsed or refractory diseases. GD2 represents a biologically relevant and clinically promising target in pediatric bone sarcomas. However, major translational challenges remain, including limited clinical data, heterogeneous study designs, and the lack of standardized assays for GD2 expression assessment. Further collaborative international studies are needed to optimize patient selection and accelerate the development of GD2-targeted combination immunotherapy strategies.