Abstract

Glioblastoma (GBM) is the most common primary brain cancer and is resistant to standard-of-care chemoradiation therapy (CRT). Magnetic hyperthermia therapy (MHT) exposes magnetic iron oxide nanoparticles (MIONPs) to an alternating magnetic field (AMF) to generate local hyperthermia. This study evaluated MHT-mediated enhancement of CRT in preclinical GBM models. Cell viability and apoptosis were assessed in GBM cell lines after water bath heating with radiation and/or temozolomide. Heating efficiency of MIONPs after intracranial delivery was measured in healthy mice. MHT with CRT was performed in syngeneic and patient-derived xenograft (PDX) GBM tumors. Tissue sections were analyzed for γ-H2AX, HSP90, CD4 + T cells, and microglial cells. Tumor burden and survival were assessed. Hyperthermia with radiation and temozolomide significantly reduced cell viability and increased apoptosis. Hyperthermia predominantly exhibited additive to synergistic interactions with both treatment modalities and reduced doses needed for tumor cell growth inhibition. In vivo, MHT with CRT decreased tumor burden and increased survival in PDX and syngeneic models. Immunohistochemistry showed increased γ-H2AX, HSP90, microglial activation, and CD4 + T cells after MHT in combination with CRT. Overall, adjuvant hyperthermia enhances CRT efficacy in GBM cells, with MHT improving survival outcomes in rodents. Sufficient intracranial heating and MIONP retention for repeated treatments was achieved, supporting further clinical translation.