Tumor Microenvironment in Neuroblastoma and Immunotherapeutic Approaches: Towards More Effective Treatment

Background/Objectives: High-risk neuroblastoma (HR-NB) is a major cause of cancer-related death among children. The review aims to discuss various biochemical and genetic traits of neuroblastoma (NB) used for the potential of cell-based therapies. Methods: A comprehensive search was performed through MEDLINE, PubMed, Scopus, and ScienceDirect using various combinations of "neuroblastoma", "tumor microenvironment (TME)", "immune cells", "non-immune cells", "hematopoietic stem cell transplantation (HSCT)", "autologous stem cell transplantation (ASCT)", "natural killer cells (NK)", "chimeric antigen receptor T cells (CAR-T)", "CAR-NKT", "tumor infiltrating lymphocytes (TIL)", "bioinformatics", and "neuro-antigens" in the published papers over the last decade. Reviews, systematic reviews, and clinical trials related to children's NB were selected. The final set included 106 articles of interest. Results: Recent studies have shown that TME is crucial in determining the malignancy, immune evasion, and drug resistance of NB. Innate immune or non-immune cells play important roles in shaping the NB TME. Depleting or reprogramming TME factors can improve the effectiveness of immunotherapy. A number of clinical trials have studied and showed feasibility of using ASCT, NK cells, CAR-T, and CAR-NKT cells in the adoptive therapy for HR-NB. However, an unambiguous evaluation of the effectiveness of cell-based technologies in the HR-NB therapy is still complicated due to the lack of large randomized trials. Conclusions: The reported small and non-randomized studies that demonstrated controversial results cannot prove, undoubtedly, the promising potential of the cell-based technologies including ASCT, NKs, CAR-T, and CAR-NKT cells. Further randomized clinical trials, using the same treatment, will help determine the role in the multimodal treatment for HR-NB.