Recently, we and others showed that MYCN-amplified NBs are characterized by a ‘cold’ TME. 11 In contrast, a T-cell infiltration-poor, ‘cold’ TME is usually associated with poor responses to immune checkpoint blockade (ICB) therapy. A hot TME is further characterized by high interferon (IFN) pathway activity, 10 a signaling cascade that plays a central role in the coordination of immune responses. 9 The latter is also known as a T-cell-inflamed or ‘hot’ tumor microenvironment (TME). Immune checkpoint inhibitors reinvigorate anti-tumor immunity depending on various parameters including tumor immunogenicity and the presence of tumor-infiltrating T cells. Monoclonal antibodies directed against programmed cell death 1 (PD-1), programmed cell death 1 ligand 1 (PD-L1) or cytotoxic T-lymphocyte associated protein 4 (CTLA-4), also known as immune checkpoint inhibitors, have significantly improved the therapy of various cancers. Serious long-term side effects caused by intensive radiochemotherapy emphasize the need for novel treatment approaches with reduced toxicity. 6 Despite these molecular insights, high-risk NB remains a major challenge in pediatric oncology. Amplification of the MYCN gene, which encodes for the oncogenic transcription factor MYCN (also known as N-Myc), was the first genomic aberration found to be associated with poor prognosis.

Activation of telomere maintenance mechanisms characterizes high-risk NB, 1 and additional alterations in the p53 or RAS pathway, known to play a role in NB pathogenesis, 2–5 further worsen disease outcome. Neuroblastoma (NB) is an extracranial solid tumor of early childhood that originates from the developing sympathetic nervous system.

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