Immune checkpoint inhibitors in pediatric central nervous system tumors: biology, clinical experience, and translational pathways to precision immunotherapy

Abstract

Purpose: Immune checkpoint inhibitors (ICI) have transformed cancer therapy but remain of limited efficacy in pediatric central nervous system tumors, which are characterized by low tumor mutational burden, sparse antigen presentation, and profoundly immunosuppressive microenvironments.

Content: Across pediatric trials, ICI monotherapy targeting the PD-1/PD-L1 axis has largely failed to show substantive benefits, underscoring the need for biomarker-driven patient selection and the identification of synergistic vulnerabilities. Recent high-dimensional profiling reveals that pediatric central nervous system tumors are not uniformly "immune cold." Subsets such as DNA replication-repair-deficient high-grade gliomas exhibit robust neoantigen burden and durable responses to PD-1 blockade, whereas data from other tumor subsets including some gliomas, germ cell tumors and select medulloblastomas demonstrate potential latent immune reactivity. Translational strategies are being developed to overcome barriers impacting ICI efficacy by studying resistance mechanisms, some of which are unique to central nervous system tumors. Potentially useful strategies to improve ICI efficacy in childhood brain tumors may involve exploration of early or neoadjuvant use, targeting non-traditional checkpoints as combination treatments, metabolic and genomic targeting for immune reprogramming, advanced drug-delivery approaches, studying and modulating the gut microbiota, improve toxicity management by limiting systemic steroid use, and parallel innovations redefining immunotherapy response assessment using advanced imaging and liquid biopsies.

Conclusion: We provide an overview of the current checkpoint inhibitor landscape for pediatric brain tumors, highlight barriers and summarize possible approaches that can be efficaciously explored in future clinical trials.

Keywords: Biomarker-guided precision immunotherapy; Immune checkpoint inhibition; Mismatch repair–deficient / replication repair–deficient glioma; Pediatric central nervous system tumors; Tumor immune microenvironment.