Neuroinflammation and proteostasis imbalance as drivers of radiotherapy-induced cognitive decline in glioma models

Cancer-related cognitive deficits (CRCDs), commonly referred to as "brain fog," represent a significant and debilitating consequence of Radiotherapy (RT) in patients with Glioblastoma (GB), IDH Wild-type (WT). While RT is essential for tumor control, the long-term molecular mechanisms underlying its induced neurotoxicity remain poorly understood, severely limiting patient quality of life. This thesis sought to define the etiology of brain fog by investigating the interplay between RT, cellular stress responses, and neuroinflammation in the brain microenvironment. Using patient-derived orthotopic xenograft (PDOX) models and in vitro co-culture systems, we uncovered a crucial biphasic cellular response to high-dose irradiation. We demonstrated that GB tumor cells attempt survival by robustly activating the Endoplasmic Reticulum (ER) stress response (ATF6, ERN1), while adjacent microglial cells exhibit hallmarks of cellular collapse. Our central finding is that high-dose RT critically compromises the microglial adaptive capacity, leading to a failure of the cellular protein quality control system. Specifically, RT suppresses key survival pathways, including the proteasome cascade, triggering the uncontrolled accumulation of misfolded proteins. This dysfunction forces the microglia into a persistent, pro-inflammatory M1 phenotype, which sustains the chronic neuroinflammation observed clinically. These results hypothesize RT neurotoxicity as a failure of microglial proteostasis and adaptive signaling, establishing a mechanistic link between radiation damage and cognitive decline. We conclude that future therapeutic strategies should adopt a dual-target approach: maintaining tumor control while simultaneously employing neuroprotective agents to shield microglial integrity and break the vicious cycle of chronic neuroinflammation, ultimately improving the long-term cognitive health of GB patients.