ABSTRACT: Neuroblastoma (NB) is a highly aggressive childhood solid tumor with poor outcomes. Chimeric antigen receptor (CAR) T cells have shown limited efficacy in NB, with the best outcomes reported in patients with a low tumor burden, highlighting the need for further CAR optimization. One approach to addressing the high tumor burden involves engineering CAR T cells to release or express transgenic cytokines. However, its systemic toxicity remains an important therapeutic challenge. Here, we evaluated the efficacy of interleukin (IL)-15- and IL-21-enhanced glypican-2 (GPC2)-targeted CAR T cells (GPC2-CAR T cells) in targeting high-burden NB. Three strategies for expressing the cytokines were evaluated: constitutive secretion (GPC2-CAR+sol.IL15.IL21), constitutive membrane-tethered expression (GPC2-CAR+teth.IL15.IL21), and NFAT-inducible membrane-tethered expression (GPC2-CAR+NFAT.IL15.IL21). Engineered GPC2-CAR T cells were tested in vitro and in vivo using high NB-burden xenograft models. Additionally, single-cell RNA sequencing was used to profile the effector cells in the tumor microenvironment. All three versions of GPC2-CAR T cells significantly enhanced killing against a high NB burden, both in vitro and in vivo, relative to control GPC2-CAR T cells. Mice treated with GPC2-CAR+NFAT.IL15.IL21 exhibited significantly lower anorexia-associated morbidity/mortality. Supporting these data, tumor-infiltrating GPC2-CAR+NFAT.IL15.IL21 developed an immunosuppressive transcriptional profile upon tumor regression, leading to prolonged survival in treated mice. In contrast, GPC2-CAR+teth.IL15.IL21 maintained a pro-inflammatory transcriptional signature despite near tumor clearance, resulting in hypercytokinemia and death. NFAT-inducible co-expression of tethered IL-15/IL-21 enhanced GPC2-CAR T-cell function against a high NB burden with acceptable tolerability in mice. Further studies are required to validate these findings.