NB is a cancer that predominantly impacts young children and emerges in nerve tissues. It frequently begins in the adrenal glands above the kidneys but can also develop in nerve tissue along the spine, chest, abdomen, or pelvis (Neuroblastoma, 1931; Qiu and Matthay, 2022; Jacobson et al., 2023). It is one of the most common cancers in infants and is typically found in children under 5 years old (Pudela et al., 2020; Davidoff, 2021; Jha et al., 2023). In the United States, around 700 to 800 children are diagnosed with NB each year, constituting about 6% of childhood cancers. The relative survival rate over 5 years for children under 15 diagnosed with NB is about 82% (Horton, 2022; Mehrvar et al., 2023). NB is classified as embryonic due to its connection to neural crest cells (NCCs) during fetal development (Ben Amar et al., 2022). NCCs are unique cells vital in early embryogenesis, migrating extensively and contributing to various tissues, including the peripheral nervous system, adrenal glands, heart, and face (Pilon, 2021). They essentially serve as building blocks for these critical anatomical features. Substantial advancements have occurred in our understanding of the molecular mechanisms underlying the development and progression of NB (Gomez et al., 2022; Ponzoni et al., 2022). These research endeavors have identified new focal points for potential treatments (Steen et al., 2023). Genome-wide studies, including genome sequencing, have unveiled fundamental genetic changes driving NB growth (Bell, 2010; Kholodenko et al., 2018a; Tonini and Capasso, 2020). In this article, we have summarized novel targets for NB, such as ISL1 (Zhang et al., 2018; Zhang et al., 2019; Li et al., 2021), DPYSL3 (Cheung et al., 2008; Chicco et al., 2023), and ROR1 (Janovská and Bryja, 2017; Quezada and Lopez-Bergami, 2023), along with immunotherapy which is an emerging and promising treatment approach for this disease. Several identified targets are currently being tested as potential treatments for NB patients. This review offers the latest molecular insights regarding the development and progression of NB with a specific focus on genetic alterations/molecular pathways along with clinical management.

Additionally, we aim to offer perspectives on the potential advantages of combination therapy, which involves using inhibitors targeting multiple pathways. One of the prominent molecular features of the NB is MYCN amplification, which is linked to aggressive tumor growth and poor prognosis, along with an increase of chromosome 17q. This oncogene is amplified in 18%–38% of total genes (Aygun and Altungoz, 2019).

Furthermore, it is expected to detect deletion involving chromosomes 1p and 11q and instances of hyperploidy in NB cases (Attiyeh et al., 2005; Bartolucci et al., 2022). Amplification of the MYCN oncogene leads to overexpression of the MYCN protein, which promotes cell growth and proliferation. Anaplastic lymphoma kinase is another oncogene. TrkA (NTRK1) is another factor linked to a favorable prognosis. It is activated by attacking the NGF ligand and promotes cell differentiation, which causes spontaneous regression of NB (Brodeur et al., 2009).

The ongoing incorporation of cutting-edge treatments for individuals with NB into clinical trials and established clinical practices has led to gradual enhancements in patient survival rates (Filippi et al., 2020). Nevertheless, survivors of high-risk neuroblastoma (HRNB) still encounter long-term side effects stemming from their treatment (Veal et al., 2021). Furthermore, there is currently no curative treatment available for most of the approximately 50% of patients who face a relapse after being diagnosed with HRNB. As diagnostic and molecular profiling technologies progress rapidly, researchers are also witnessing the identification of potential targets for treatment (Advani et al., 2022). Molecular targeted therapy for genomic abnormalities and disrupted pathways offers a promising and innovative approach to NB treatment (Jones et al., 2019; Voicu et al., 2023). This approach holds the potential to enhance treatment effectiveness while minimizing adverse effects. In this context, we have explored the clinical scenario regarding NB therapies within the precision medicine framework. Substantial progress has been achieved in understanding the molecular causes of NB, revealing potential therapeutic targets. Genomic studies have identified genetic changes and disrupted pathways in NB growth. These findings may lead to more effective, less toxic treatments.

Authors also delve into their examination in ongoing clinical trials. Furthermore, future directions have been added for enhancing or creating more effective targeted therapies to improve the survival rates of NB patients while minimizing treatment-related side effects.

NB represents the predominant solid tumors outside the cranial cavity during childhood, particularly prevalent within the first year of life (Park et al., 2010; Irwin and Park, 2015). Its distinctive nature is that infants frequently manifest either localized or metastatic forms of the disease, which may undergo spontaneous regression intervention (Tolbert and Matthay, 2018). In contrast, older children can experience disease progression leading to morbidity or mortality despite prolonged and intensive therapeutic interventions (Ahmed et al., 2017). The “International Neuroblastoma Risk Group Staging System (INRGSS)" is a classification system employed in the medical field to stage and categorize NB (Monclair et al., 2009; Sokol and Desai, 2019; Irwin et al., 2021). NB exhibits significant variability, making it crucial to have a systematic approach to determine the disease’s extent and guide treatment choices. There are various known molecular aspects in NB, such as MYCN amplification, ALK mutations, chromosomal abnormalities (Carén et al., 2008), changes in the pattern of DNA methylation, and tumor microenvironment (Tonini and Capasso, 2020; Raieli et al., 2021). Interactions of the tumor microenvironment with stromal cells and blood vessels also play a crucial role in NB progression. Neutrophins are other growth factors involved in developing and maintaining the nervous system, and their dysregulation further promotes tumor growth and survival.

Over 50 years ago, Conrad Waddington introduced the foundational principles of the ‘epigenetic landscape’ to elucidate the fundamental mechanisms governing normal cell differentiation (Baedke, 2013). These studies revealed that transcription factors play pivotal roles in shaping and directing cellular identity and navigating developmental pathways on Waddington’s Hill. Interactions with diverse DNA regulatory elements within a specific epigenetic framework, coupled with chromatin, contribute to the stability of cellular lineages and fates, akin to the depth of grooves on the developmental hill. In a recent analysis, Flavahan and colleagues proposed the notion of aberrant epigenetic resistance and plasticity, attributing these phenomena to dysregulated chromatin regulator activity, remodeling, and DNA methylation as crucial contributors to tumorigenesis (Flavahan et al., 2017; Durinck and Speleman, 2018). Management approaches for asymptomatic individuals classified as low risk, with a projected survival rate exceeding 98%, typically entail either observation or surgical excision alone.

Conversely, intermediate-risk patients, characterized by a survival rate exceeding 90%, necessitate moderate doses of chemotherapy tailored to their response alongside surgical resection (Pinto et al., 2015). Patients classified as high risk undergo successive cycles of combination chemotherapy preceding surgical intervention, followed by consolidation therapy involving myeloablative autologous hematopoietic stem cell transplantation and localized radiation therapy (Tolbert and Matthay, 2018). Subsequently, the patients receive immunotherapy and differentiation therapy during the maintenance phase. The INRGSS incorporates tumor characteristics, metastasis, patient age, and specific biological markers (Newman et al., 2019; Campbell et al., 2023). Figure 1 displays the schematic summary between high-risk and low-risk neuroblastoma. Below is a detailed overview of the stages and risk groups in the INRGSS.

- Stage L1: This stage denotes NB confined to its origin point and has not spread to distant sites (Luksch et al., 2016). Tumors in this stage usually exhibit less aggressive biological features, indicating a more favorable prognosis. Patients in stage L1 are considered low-risk and typically have better treatment outcomes (Newman et al., 2019).

The positive outcomes observed in immunotherapy involving anti-GD2 monoclonal antibodies prompt an inquiry into whether NB possesses characteristics that make it susceptible to immune responses (Bhoopathi et al., 2021; Morandi et al., 2021). When discussing the immunogenicity of NB, it is essential to be precise in terminology (Webb et al., 2020; Paraboschi et al., 2021). If we consider “immunogenicity” in the context of cancer, the question arises as to whether NB can activate immune responses.

Despite the absence of evidence for an adaptive immune response, a substantial body of evidence indicates that NB, like many other human cancers, possesses inherent mechanisms designed to elude immune recognition (Cervantes-Villagrana et al., 2020). These mechanisms include decreased MHC class-I expression, suppressive myeloid cells, and the production of inhibitory factors like arginase-2 and TGF-β (Cornel et al., 2020; Dhatchinamoorthy et al., 2021). It enhances an intriguing possibility that the relatively low immune activity within NB may result from a lack of inherent danger signals and the tumor’s active immune evasion mechanisms. This observation offers hope for the potential effectiveness of immunotherapeutic strategies. By developing therapeutic approaches capable of targeting NB cells, scientists have managed to induce a novel immune response in tumors that otherwise appear to escape detection by the natural immune system. These immunotherapies, which utilize synthetic immune recognition, are frequently based on monoclonal antibodies (Carazas et al., 2021; Varadé et al., 2021). Monoclonal antibodies designed to target the disialoganglioside GD2, commonly overexpressed on most NB cells, have brought about a transformative impact on the treatment of NB (Hung and Alice, 2019). They have led to a remarkable increase in event-free survival rates, as high as 20%.

Furthermore, synthetic recognition agents can be further developed from antibody derivatives, including CAR-T cells and antibody-drug conjugates. These innovative therapeutic approaches have demonstrated promising results in pre-clinical and early clinical trials, signifying a significant advancement in immunotherapy. TGF-β regulates cellular activities, including controlling cell growth, proliferation, differentiation, and apoptosis. TGF-β was initially thought to inhibit cancer, but recent studies show it can also promote cancer by impairing NK cell function, leading to increased tumorigenesis, metastasis, and drug resistance, which is a promising target for immunotherapy (Slattery and Gardiner, 2019; Wang et al., 2021; Wienke et al., 2021). Table 2 comprises various immunotherapy approaches to combat NB.

In conclusion, the comprehensive review of NB underscores the significance of diverse therapeutic targets, including ISL1, DPYSL3, MDM2-p53, and ROR1. The exploration of these targets has provided valuable insights into potential avenues for interventions in this cancer. The outcomes of clinical trials and other therapies hold evidence for advancing precision medicine. Identifying additional valuable targets and creating more efficient therapies are imperative. Furthermore, delving into novel combinations that incorporate inhibitors addressing multiple targets in conjunction with conventional treatments remains a paramount focus for future research. This direction is poised to advance treatment protocols, enhance results, and extend the survival of high-risk NB in children. Although significant breakthroughs have been achieved in molecularly targeted therapy for NB, applying these findings to clinical disease management has had limited success in previous years. Thus far, the sole approved treatment for pediatric patients with relapsed or refractory HRNB is anti-GD2 monoclonal antibodies. The disparity between research conducted in pre-clinical settings and its translation into clinical trials is striking. There is also a need for novel combinations to target multiple molecular targets in conjunction with traditional therapies.

NB, a childhood cancer, is characterized by abnormal development and typically has a low mutational burden, distinguishing it from most adult malignancies. Conversely, drug testing primarily relies on conventional NB cell and mouse models. There is a need to progress towards developing new disease models by harnessing cutting-edge technologies, like 3D tissue-engineered systems and patient-derived xenograft model systems. Researchers must focus on in vitro and in vivo testing studies to develop new synthetic drugs to treat NB. Further research must be carried out on designing novel inhibitors and immunotherapy. Apart from discovering novel targets for immunotherapy and designing therapeutic interventions, researchers must also prioritize designing a combination of new small NB inhibitors with radiotherapy to inhibit the various signaling pathways. Decreasing the high dose of radiochemotherpeutic agents could be another significant approach to combat NB without toxicity and side effects. New target-based inhibitors are being used for the patients. In summary, the future of immunotherapy and novel targeted therapies in NB treatment is marked by a commitment to innovation, personalization, and collaboration. With ongoing research and technological advancements, people can expect improved outcomes and quality of life for NB patients in the years to come.