Exploring the effects of ROS on PI3K/AKT/mTOR signalling in pediatric low-grade glioma and therapeutic strategies

Pediatric low-grade gliomas (pLGGs) are the most common central nervous system tumors in children. Although typically slow-growing, they pose major clinical challenges, including recurrence and treatment resistance. Emerging evidence identifies oxidative stress (OS) and dysregulation of the PI3K/AKT/mTOR (PAM) signaling pathway as central drivers of pLGG pathogenesis. This review explores the interplay between redox imbalance and PAM signaling, focusing on the dual role of reactive oxygen species (ROS) in tumor biology. Physiologically, ROS are vital for normal cellular signaling; however, excessive accumulation promotes oncogenesis by activating PAM and NF-κB pathways while suppressing tumor suppressors such as PTEN. Paradoxically, ROS can also initiate autophagy, ferroptosis, and apoptosis, offering therapeutic opportunities. This dual role positions ROS as both a tumor promoter and a therapeutic lever. Strategies under investigation include pro-oxidant therapies, ROS-sensitive drug delivery systems, ROS-activated agents, and targeted PAM inhibitors such as everolimus and dual-targeting compounds like samotolisib. Therapeutic choice is context-specific: if ROS is facilitating tumor survival through PI3K/AKT activation, combination with mTOR inhibitors could be best; if ROS initiates pro-apoptotic signaling, ROS-generating strategies, including certain chemotherapies, could be better. Pediatric-specific factors-metabolic distinctions, antioxidant defenses, and sensitivities during development-requires careful dosing and close safety monitoring. ROS-mediated PAM signaling modulation provides a promising, mechanism-based therapeutic pathway for pLGG. Combinations of redox-targeted approaches with molecular characterization and current therapies have the potential to increase precision, efficacy, and safety, eventually leading to better survival and quality of life for the involved children.