Cancer is the leading cause of death in children and adolescents. Standard treatments which include surgery, chemotherapy, radiation, and stem cell transplantation, are barely effective. Still, these therapeutic regimens are well-known to cause highly toxic and long-lasting side effects, including secondary cancers, which are far from acceptable considering the young age of patients. Moreover, therapy resistance is common, often leading to cancer relapse and metastasis. Recent advancements in cancer treatments for adults have not been mirrored in pediatric oncology, highlighting a critical gap in the field. As such, there is an urgent need to develop safer and more innovative treatment strategies tailored for children with cancer.

In this vein, this Research Topic seeks to address this gap focusing on a variety of pediatric cancers, with the aim of enhancing our understanding and promoting the development of innovative therapeutic approaches, to finally improve patient’s outcomes and quality of life.

Cancer immunotherapy has revolutionized the approach to cancer treatment by restoring or reactivating the immune system's ability to fight tumors. Various immunotherapeutic strategies, such as vaccines, cell therapies (e.g., CAR-T and CAR-NK), and immune checkpoint inhibitors, have shown significant promise; however, their potential remains not fully realized, especially in pediatric cancers, where immunotherapy advancements have lagged behind those for adult ones. As a result, treatments including surgery, chemotherapy, and radiotherapy have remained the standard of care for many pediatric cancers, despite their significant long-term toxicities and side effects. Recent evidence has highlighted that monotherapies - whether conventional or immune-based - are insufficient in overcoming the complex tumor heterogeneity and resistance mechanisms. Combining various immunotherapies, along with integrating them into traditional treatment regimens, offers a promising strategy to tackle tumors from multiple angles. This approach is critical for pediatric cancers, where innovative, safe, and rationally-designed combinatory strategies are urgently needed, to ultimately improve survival rates and quality of life for young patients.

This Research Topic aims to explore innovative approaches to enhance the efficacy of immunotherapy for pediatric cancers, while limiting off-target and adverse effects of conventional treatments, with a particular focus on combinatorial strategies. Given the limitations of monotherapies in treating pediatric cancers, and the complex nature of tumor heterogeneity and resistance, contributors are invited to present original research, reviews, and perspectives that address key challenges and opportunities in integrating immunotherapy with conventional treatments. Topics and areas of interest include, but are not limited to:

• Identification of novel drug targets for immunotherapy in pediatric cancers

• Reliable preclinical models of pediatric cancers and for testing novel therapeutic combinations

• Combination strategies in pediatric cancer immunotherapy

- Synergistic effects of combining different immunotherapies (e.g., checkpoint inhibitors with CAR-T, cancer vaccines with NK-cell therapies)
- Pre-clinical and clinical studies evaluating immunotherapy combinations: real-world evidence and retrospective analyses of combination approaches; regulatory and logistical challenges in implementing combination immunotherapies
- Strategies to mitigate immune-related adverse events in combination therapies
- Biomarker-driven approaches for selecting optimal immunotherapy combinations

• Mechanisms of resistance to therapy and combinatorial strategies to overcome resistance in pediatric cancers

- Immune evasion strategies employed by tumors
- Mechanisms underlying primary and acquired resistance to checkpoint inhibitors, CAR-T, and other immunotherapies
- Role of the tumor microenvironment in shaping immune responses

Overall, this Research Topic seeks to foster interdisciplinary discussions and drive new insights into how we can improve pediatric cancer treatment through well-designed, integrative approaches. Contributions spanning basic research, translational science, and clinical applications are highly encouraged.

Are you interested in contributing a manuscript to this Research Topic?

Next-Generation Treatment for Pediatric Cancer: Advancing Immunotherapy through Combinations