Single-cell transcriptomic atlas-guided NRG3-ERBB4 axis enhances the efficacy of chemo-immunotherapy during induction phase in high-risk neuroblastoma.

Chemo-immunotherapy (CI) administered during the induction phase markedly ameliorates immune responses and improves clinical efficacy in patients with high-risk neuroblastoma (NB), yet the underlying translational mechanisms remain poorly defined. Single-cell transcriptomic analysis revealed selective activation of the NRG3-ERBB4 axis in pretreatment tumor specimens from high-risk NB patients, accompanied by augmented cytotoxic programs in CD8+ T cells and natural killer cells. During induction therapy, chemotherapy alone suppressed NRG3 and ERBB4 expression, whereas their levels were significantly upregulated upon the addition of naxitamab and positively correlated with NB-reactive immune responses. Functional assays further confirmed that NB cells exposed to CI activated NRG3-ERBB4 signaling, which in turn induced the upregulation of GZMB and GNLY in effector lymphocytes. Integrated analysis of bulk RNA sequencing and lipidomics further demonstrated that the NRG3-ERBB4 rewired ganglioside metabolism to limit its intratumoral accumulation, thereby restoring tumor-reactive immune surveillance. Collectively, these findings delineate an NRG3-ERBB4 axis-centered tumor-immune crosstalk that operates across pretreatment, chemotherapy, and CI, uncovering a previously unrecognized mechanism underlying naxitamab-mediated immune activation. Our results also support ERBB4 as a promising predictive biomarker and therapeutic target to optimize CI strategies for high-risk NB.