Editorial: The Immunosuppressive Microenvironment in Pediatric Cancers: Applications and Considerations in Immunotherapy

Jiaxiong Tan ^1* Fei Gao ² Ling Xu ³

• ¹ National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
• ² Brown Center for Immunotherapy, Department of Medicine, School of Medicine, Indiana University Bloomington, Indianapolis, Indiana, United States
• ³ Institute of Hematology, School of Medicine, Jinan University, Guangzhou, China

Immunotherapy has truly transformed the landscape of cancer treatment, bringing about remarkable improvements in survival rates across a wide spectrum of adult cancers. However, the so far in the pediatric cohort have been disappointing, largely due to differences in tumor biology, including high heterogeneity in the tumor immune microenvironment and generally low tumor mutation burden. These microenvironments, populated by immunosuppressive cells such as regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), and tumor-associated macrophages (TAMs), dampen the immune response against tumors and a series of complex molecular pathways drive tumor progression and drug resistance [1][2][3].Understanding and targeting these immunosuppressive mechanisms is crucial for developing effective immunotherapeutic strategies in pediatric cancers.In their paper titled "Mechanisms and Molecular Characterization of Relapsed/Refractory Neuroblastomas", Zixuan Wei and colleagues provide a thorough and insightful review of the complex molecular pathways driving relapsed and refractory neuroblastomas -a pediatric cancer with a particularly grim prognosis. The authors highlight key molecular alterations, including MYCN amplification, ALK mutations, TERT promoter mutations, p53 pathway inactivation, and chromosomal instability, which contribute to the immunosuppressive microenvironment and therapeutic resistance. These molecular changes not only drive tumor progression but also create an environment hostile to immune cells, thereby limiting the effectiveness of immunotherapies. The review emphasizes the potential of precision medicine approaches targeting these molecular mechanisms to improve treatment outcomes, suggesting that combining immunotherapy with targeted therapies could enhance efficacy. Notably, MYCN amplification occurs in one-third of high-risk neuroblastomas [4]. However, MYCN is a transcription factor and Intrinsically Disordered Proteins (IDPs), which makes it difficult to target MYCN directly [4,5]. CRGs associated with patient outcomes, demonstrating significant differences in immune cell infiltration and drug sensitivity between high-risk and low-risk groups. In addition, cuproptosis-related genes, calponin 3 (CNN3) and leucine-rich repeat-containing G-protein-coupled receptor 4 (LGR4, also called GPR48) were identified as modulators of cAML progression, and they were shown to be associated with immune cell infiltration ，making them potential therapeutic targets. This research highlights the importance of understanding the molecular mechanisms of cell death in cancer cells, providing new insights into personalized treatment strategies for cAML. Additionally, the study underscores the importance of considering age-specific differences in immune landscapes when developing immunotherapies for pediatric cancers. In study titled "TRIM8 as a predictor for prognosis in childhood acute lymphoblastic leukemia based on a signature of neutrophil extracellular traps", Waihin Tin et al. explored the prognostic value of neutrophil extracellular traps (NETs) in childhood acute lymphoblastic leukemia (cALL). The study identifies TRIM8 as a key gene associated with NETs and demonstrates its role in leukemia cell proliferation and prognosis. The findings suggest that TRIM8 knockdown improves outcomes in ALL models. The study also provides insights into the relationship between NET-related genes and immune cell communication, suggesting that targeting NETs could enhance immunotherapy efficacy. This research underscores the importance of understanding the complex interactions between cancer cells and the immune system, particularly in the context of pediatric cancers, where the immunosuppressive microenvironment poses significant challenges to treatment. This research topic covers advances in immunology, genomics, and bioinformatics in common childhood tumors such as neuroblastoma, cAML, and cALL. Among the seven articles submitted, four were accepted for publication, comprising two reviews and two original research articles. These contributions collectively offer novel insights into the immunosuppressive microenvironment and immunotherapy in pediatric tumors, aiming to lay a foundation for advancing the application and therapeutic efficacy of immunotherapy in this vulnerable patient population. It is our hope that the content of this special topic will not only inspire readers but also draw increased attention from researchers to the unique challenges and opportunities presented by childhood tumors, ultimately driving forward more valuable research progress in this field.