Tumor Treating Fields and the Glioblastoma Microenvironment: Mechanistic Convergences with Radiotherapy

Glioblastoma (GBM) remains the most lethal primary brain tumor in adults, with a median overall survival of approximately 15-20 months despite multimodal treatment including surgery, chemoradiation, and Tumor Treating Fields (TTFields). While the survival benefit of TTFields was established by the EF-14 phase III trial, their biological effects extend well beyond the canonical anti-mitotic mechanism and encompass extensive interactions with the GBM tumor microenvironment (TME). This review provides an integrated mechanistic analysis of TTFields-TME interactions in GBM, with a distinctive focus on their convergence with radiotherapy. We examine how TTFields activate innate immune sensing through cGAS/STING and AIM2 inflammasome pathways, drive immunogenic cell death, reprogram tumor-associated macrophages, and prime adaptive T cell responses. We further address TTFields effects on glioma stem cells, blood-brain barrier permeability, and intracellular signaling governing invasion, angiogenesis, and autophagy. Critically, we develop the mechanistic and clinical case for TTFields-radiotherapy combinations, highlighting convergent mechanisms of DNA repair impairment, mitotic catastrophe, and innate immune activation. Practical considerations for concurrent clinical implementation are discussed alongside a research agenda centered on optimal timing, hypofractionation, and predictive biomarkers. Available evidence-largely preclinical-suggests that TTFields may act as a TME-remodeling platform whose potential is most likely to be realized through mechanistically informed combinations.