GPC2 (glypican 2) is a cell surface heparan sulfate proteoglycan involved in neurodevelopment and prominently expressed in multiple malignancies. 1 GPC2 is a GPI-anchored proteoglycan with functions related to cell migration and neuron projection development, particularly during fetal development. 2 In cancer biology, GPC2 serves as a diagnostic and prognostic biomarker across multiple tumor types. 1 Pan-cancer analysis demonstrates that GPC2 is highly expressed in most malignancies (except pancreatic adenocarcinoma) and shows early diagnostic value in 16 tumor types, with expression significantly correlated to immune cell infiltration and DNA methylation patterns. 1 GPC2 has emerged as a critical therapeutic target in pediatric solid tumors, particularly high-risk neuroblastoma, which expresses clinically relevant GPC2 antigen density (~5,000 molecules/cell). 2 Engineered GPC2-directed CAR T cells demonstrate potent efficacy against neuroblastoma expressing native antigen densities without toxicity when optimized for low antigen threshold. 2 GPC2-CAR T cells also show activity against pediatric brain tumors including medulloblastomas and gliomas. 3 Recent advances incorporating cytokine co-expression and innate immune cell engagement further enhance GPC2-CAR T-cell function against high-burden disease. 4 GPC2 expression is tumor-specific, driven by E2F1 transcription factor activity, making it an attractive immunotherapeutic target. 5