CCL2: A double-edged sword in neuroblastoma, with a critical role in MYCN-amplified tumors

• In neuroblastoma, MYCN amplification suppresses CCL2, creating an immune-cold microenvironment. • CCL2 shapes immune cell recruitment and balance in neuroblastoma tumors. • Low CCL2 limits immune surveillance in high-risk MYCN-amplified NB. • CCL2/CCR2 targeting improves CAR-T trafficking and reduces TAM suppression. Neuroblastoma (NB) is the most common extracranial solid tumor in children, characterized by significant clinical heterogeneity and immune evasion. MYCN oncogene amplification is a major driver of tumor aggressiveness and poor prognosis and is inversely correlated with immune infiltration in the tumor microenvironment (TME). Emerging evidence highlights the pivotal role of the chemokine C-C motif ligand 2 (CCL2) in modulating the immune landscape of NB. CCL2 influences the recruitment of various immune cells, including invariant natural killer T (iNKT) cells, dendritic cells (DCs), monocytes, macrophages, and regulatory T cells (Tregs), thereby shaping either pro- or anti-tumor responses depending on the context. MYCN -amplified tumors display reduced CCL2 expression, resulting in limited immune cell recruitment and the establishment of a “cold” TME with poor immune surveillance. In contrast, non-amplified tumors exhibit higher levels of CCL2, which attracts both anti-tumor immune cells such as DCs and macrophages, as well as pro-tumor populations including Tregs and tumor-associated macrophages (TAMs). These observations underscore the dual and context-dependent role of CCL2 in NB pathogenesis. Therapeutically, targeting the CCL2/CCR2 axis has shown promise in preclinical models, including approaches to enhance CAR-T cell trafficking and reduce TAM-mediated immunosuppression. Overall, CCL2 emerges as a central immunomodulatory molecule in NB, tightly linked to MYCN status and the composition of the TME. Understanding its complex biology is critical for the development of novel immunotherapies aimed at restoring effective anti-tumor immune responses, particularly in high-risk MYCN -amplified NB. Targeting the CCL2 axis represents a promising strategy to improve NB patient outcomes.