Interplay Between the Epigenome, the Microenvironment, and the Immune System in Neuroblastoma

TL;DR

This review explores how the epigenome, tumor microenvironment, and immune system interact in neuroblastoma to identify new treatment strategies for high-risk patients.

Contribution

The paper provides an integrated synthesis of mechanisms driving neuroblastoma progression and highlights novel therapeutic strategies targeting these mechanisms.

Findings

Current treatments for high-risk neuroblastoma have limited efficacy and significant side effects.

Novel therapies targeting genetics, epigenetics, and the immune system are being explored to improve outcomes.

Preclinical and clinical studies suggest potential in using immunotherapy and cell-engineering techniques for neuroblastoma.

Abstract

Neuroblastoma (NB) remains a clinically challenging cancer with high heterogeneity and poor outcomes in high-risk patients. The aim of this review is to provide an integrated synthesis of the key mechanisms that drive NB progression, particularly oncogenes, epigenetic regulators, and the tumor microenvironment, and how they can be targeted with current therapeutic strategies, including immunotherapy. By examining how these mechanisms contribute to NB progression and treatment resistance, this review highlights opportunities for developing more effective and rationally designed combination therapies. Ultimately, this work seeks to propose future research directions that could improve therapeutic outcomes for children affected by this aggressive disease.

Neuroblastoma (NB) is the most prevalent extracranial childhood tumor and the third leading cause of death from cancer in children. Despite having a high overall survival rate for low- and intermediate-risk patients, survival rates for high-risk cases remain unsatisfactory. The current standard treatment for high-risk NB involves surgery, chemotherapy, radiotherapy, autologous stem cell transplantation, immunotherapy with anti-ganglioside GD2, and differentiation therapy with isotretinoin. Besides not being enough to achieve a high survival rate in high-risk patients, these treatments are associated with significant side effects. With next-generation sequencing technologies, a better understanding of the genetic and epigenetic landscapes of NB has been achieved. This has led to the study of novel treatments to improve the overall survival rate of high-risk NB and reduce the toxicity of conventional treatments. Current research is focusing on the development of targeted drugs for genetic and epigenetic alterations, and protein degraders. Moreover, immunotherapy to enhance anticancer immune responses and by using cell-engineering techniques with chimeric antigen receptor (CAR) T and NK cells are being explored to target NB cells. Here, we review promising novel treatment strategies for NB, which target genetics, epigenetics, the tumor microenvironment, and the immune landscape, highlighting preclinical studies and ongoing clinical trials.

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