Melaud Elahi

Background: Glioblastoma (GBM) is an aggressive tumor of the central nervous system that is difficult to treat due to its ability to rapidly invade surrounding brain tissue.¹ These mutated cells take advantage of cytoskeletal changes and intercellular communication, leading to diffuse invasion within the brain and resulting in headaches, seizures, neurological deficits, and a median survival rate of 14-18 months for the patient.^1,2 Currently, standard therapy involves maximum safe tumor resection, followed by radiotherapy and Temozolomide (TMZ) chemotherapy.^1,3 However, recurrence is largely inevitable, due to the intrinsic and acquired resistance mechanisms of GBM cells.⁴ However, recent studies have shown Tumor Treating Fields (TTFs) to be a noninvasive treatment that uses alternating electrical fields to target these resistance mechanisms, suggesting an opportunity to strengthen current GBM therapies with adjuvant application of TTFs.^5-9

Objective: This narrative review examines the mechanisms by which TTFs improve GBM outcomes and assess its effectiveness when used in combination with traditional chemotherapy.

Search Methods: This review was based on literature published between 2018 to 2025 in the online PubMed database. Keywords such as “glioblastoma”, “tumor treating fields”, “pathogenesis”, and “overall survival” were used to find the references.

Results: In-vitro and organoid studies indicate that TTFs applied at a frequency of 200 kHz reduced GBM cell density and damaged filamentous actin, microvesicles, and gap junctions.⁵ A 71.4% decrease in Ca²⁺ transients was observed, indicating a significant reduction in intercellular communication and tumor network connectivity.⁵ Additional experiments demonstrated that TTFs promote phosphorylation of GEF-H1, resulting in downstream inactivation of the RhoA G-protein, which is otherwise key in microtubule and actin cytoskeleton organization.⁶ A subsequent reduction in the speed of GBM migration in surrounding brain tissue was revealed, indicating a disruption in cellular motility.⁶ TTFs also induced nuclear envelope rupture and cytoplasmic DNA leakage in GBM cells, activating the cGAS/STING and AIM2 inflammasome pathways.⁷ This stimulated the innate immune system to increase recruitment of proinflammatory cytokines, type 1 interferons, as well as CD8⁺ cytotoxic T-cells.⁷ In MGMT-methylated GBM cell lines, TTFs enhanced the cytotoxic effects of alkylating agents such as TMZ and Lomustine by downregulating the FA-BRCA DNA repair pathway, while increasing unrepaired double-stranded DNA breaks and the likelihood of apoptosis.⁸ Clinically, a phase 2 study found that adding Pembrolizumab to TTFs and TMZ was well-tolerated and resulted in median progression free survival (PFS) of 12.0 months compared with 5.8 months in controls, as well as median overall survival (OS) of 24.8 months compared with 14.6 months in controls.⁹

Conclusion: TTFs function as a strong adjuvant therapy for GBM by targeting cellular growth mechanisms such as mitosis, motility, and intercellular communication. Additionally, TTFs have shown to activate the innate immune response and suppress tumor DNA repair capabilities following chemotherapy administration. Therefore, the evidence supports further randomized clinical trials to solidify the frequency, duration, and patient selection criteria of TTFs when used in combination with traditional chemotherapy for GBM treatment.

Works Cited:

1. Królikowska K, Błaszczak K, Ławicki S, Zajkowska M, Gudowska-Sawczuk M. Glioblastoma-A Contemporary Overview of Epidemiology, Classification, Pathogenesis, Diagnosis, and Treatment: A Review Article. Int J Mol Sci. 2025;26(24):12162. Published 2025 Dec 18. doi:10.3390/ijms262412162
2. Ostrom QT, Cioffi G, Waite K, Kruchko C, Barnholtz-Sloan JS. CBTRUS Statistical Report: Primary Brain and Other Central Nervous System Tumors Diagnosed in the United States in 2014-2018. Neuro Oncol. 2021;23(12 Suppl 2):iii1-iii105. doi:10.1093/neuonc/noab200
3. Schaff LR, Mellinghoff IK. Glioblastoma and Other Primary Brain Malignancies in Adults: A Review. JAMA.2023;329(7):574–587. doi:10.1001/jama.2023.0023
4. Binabaj MM, Bahrami A, ShahidSales S, et al. The prognostic value of MGMT promoter methylation in glioblastoma: A meta-analysis of clinical trials. J Cell Physiol. 2018;233(1):378-386. doi:10.1002/jcp.25896
5. Schlieper-Scherf S, Hebach N, Hausmann D, et al. Disrupting glioblastoma networks with tumor treating fields (TTFields) in in vitro models. J Neurooncol. 2024;170(1):139-151. doi:10.1007/s11060-024-04786-0
6. Voloshin T, Schneiderman RS, Volodin A, et al. Tumor Treating Fields (TTFields) Hinder Cancer Cell Motility through Regulation of Microtubule and Acting Dynamics. Cancers (Basel). 2020;12(10):3016. doi:10.3390/cancers12103016
7. Chen D, Le SB, Hutchinson TE, et al. Tumor Treating Fields dually activate STING and AIM2 inflammasomes to induce adjuvant immunity in glioblastoma. J Clin Invest. 2022;132(8):e149258. doi:10.1172/JCI149258
8. Fishman H, Monin R, Dor-On E, et al. Tumor Treating Fields (TTFields) increase the effectiveness of temozolomide and lomustine in glioblastoma cell lines. J Neurooncol. 2023;163(1):83-94. doi:10.1007/s11060-023-04308-4
9. Chen D, Le SB, Ghiaseddin AP, et al. Efficacy and safety of adjuvant TTFields plus pembrolizumab and temozolomide in newly diagnosed glioblastoma: A phase 2 study. Med. 2025;6(9):100708. doi:10.1016/j.medj.2025.100708