Targeting Lactate import to enhance Ferroptosis sensitivity in Medulloblastoma

Medulloblastoma is one of the most aggressive pediatric tumours of the central nervous system and is associated with a poor prognosis, exacerbated by frequent relapse and therapeutic resistance. Like many brain tumours, it exhibits extensive hypoxic regions that drive marked metabolic remodelling, favouring aerobic glycolysis and resulting in lactate accumulation within the tumour microenvironment. This metabolite is not merely a glycolytic byproduct, but an important modulator that promotes proliferation, invasiveness, and resistance to oxidative stress. Since ferroptosis, a form of iron-dependent cell death characterized by lipid peroxidation, represents a promising therapeutic vulnerability for tumours under high oxidative stress, this project explored the role of lactate in modulating ferroptosis in medulloblastoma. In the initial phase, the protective effect of lactate was assessed using both exogenous lactate supplementation and conditioned medium derived from immortalized human astrocytes, modelling an Astrocyte Neuron Lactate Shuttle (ANLS)-like system to simulate physiological lactate supply from astrocytes. Subsequently, the focus shifted to lactate transport, specifically the role of MCT1, through pharmacological inhibition using AZD3965 and gene silencing via viral vectors. In both approaches, inhibition of MCT1 abolished the protective effect of lactate, suggesting that intracellular lactate transport is essential for conferring resistance to ferroptosis. The results demonstrate that lactate, whether exogenous or microenvironment-derived, exerts a protective effect against ferroptosis induction, and that this protection relies primarily on its uptake into the cell via MCT1. Overall, this project highlights how lactate metabolism and interactions with the tumour microenvironment critically contribute to ferroptosis resistance in medulloblastoma, identifying MCT1 as a potential therapeutic target.