AIMS We aim to improve treatment outcomes and reduce long-term brain damage after radiotherapy in patients treated for high-grade brain tumours. We have found that lithium (Li) can serve this dual purpose. We explore the underlying mechanisms and work towards including lithium in future treatment protocols. BACKGROUND Radiotherapy (RT) to the brain results in late-appearing complications, especially in children. The cognitive deficits are particularly debilitating. There are currently no established treatments to prevent or reverse these conditions. WORK PLAN To optimise treatment strategies, we need to characterise the protective effects of Li treatment on different cellular populations in the healthy brain. Using mouse models and human tumour cells, we explore how Li prevents the growth of medulloblastoma and high-grade glioma. PRELIMINARY RESULTS Li effectively prevents the growth of tumour cells in a mouse model of group 3 medulloblastoma and hemispheric high-grade glioma, tumours with poor prognosis, by upregulating the tumour suppressor Klf4 and blocking cell cycle progression. Li prevents the RT-induced loss of hippocampal gamma oscillations over time, at least partly by promoting the survival of neurons and rewiring the transcriptional profile of microglia. METHODS We use mouse models of paediatric high-grade brain tumours and cranial RT, combined with patient samples (blood, tumour, and brain tissues). Single-cell RNA sequencing and modern bioinformatics tools help characterise the complex interactions within tumour and brain tissues. CLINICAL SIGNIFICANCE Li can potentially improve tumour treatment outcomes and protect normal brain tissue from the adverse effects of RT. Suppose we can prevent or reduce the late complications induced by their treatments. If so, we will improve the quality of life of our survivors and their families and reduce the burden on society.