Glioblastoma is the most common and deadliest brain cancer in adults despite intensive therapy. Tumor-treating fields at 200 kHz were recently approved in combination with temozolomide for the treatment of newly diagnosed GBM. The addition of TTF resulted in a significant improvement in overall survival. Early this year, TTF also received approval for the treatment of mesothelioma and are actively being tested in late staged clinical trials in other cancers. TTF are low intensity alternating electric fields thought to disturb mitotic macromolecules’ assembly, leading to disrupted chromosomal segregation and apoptotic cell death. Although resistance develops in most TTF responders, its molecular mechanism remains unexplored. This proposal aims to understand how GBM cells circumvent the biophysical insults caused by TTF and their downstream effects, providing new opportunities to improve efficacy of this novel anti-cancer modality.