SFRP2+ fibroblasts orchestrate post-chemotherapy remodeling and define a tumor-driven prognostic program, NBTRP, in adrenal neuroblastoma

Abstract

Neuroblastoma (NB) is a highly heterogeneous pediatric cancer in which chemotherapy resistance and poor prognosis are tightly linked to the tumor microenvironment (TME). Yet, how chemotherapy reshapes stromal components, particularly cancer-associated fibroblasts (CAFs), and the clinical implications of these alterations remain unclear. Here, by integrating single-cell, spatial, and bulk RNA-seq data from nine NB datasets, we systematically characterized chemotherapy-induced TME remodeling. Fibroblast subtypes were defined through clustering, stemness estimation, and functional enrichment analyses, revealing SFRP2 + inflammatory CAFs (iCAFs) as the dominant fibroblast population enriched after chemotherapy in adrenal NB TME. These SFRP2 + iCAFs exhibited high expression of SFRP2, FBLN1, and chemokines CXCL2 and CXCL3, and were found to promote angiogenesis by signaling to endothelial cells through the CCL2/CXCL2/3/8–ACKR1 axis. Building on the chemotherapy-associated gene expression changes in adrenal NB tumor cells, we developed a 6-gene prognostic model, termed NBTRP. The NBTRP robustly stratified patient survival across multiple cohorts and was associated with reduced cytotoxic T cell infiltration, increased tumor purity, and distinct drug sensitivity profiles. High NBTRP scores predicted enhanced sensitivity to chemotherapeutic agents such as vinblastine and etoposide, as well as improved response to anti–PD-L1 immunotherapy. Functional validation further identified SERPINF1, the top NBTRP feature, as a key effector that promoted NB cell invasion in vitro and modulated drug responses to vincristine, etoposide, cisplatin and cyclophosphamide. Together, our findings uncover SFRP2 + iCAFs as pivotal mediators of post-chemotherapy TME remodeling and establish NBTRP and SERPINF1 as clinically relevant biomarkers that bridge tumor–stroma dynamics with prognosis and therapeutic guidance in adrenal neuroblastoma.