Abigail Contreras

Background: Glioblastoma (GBM) is the most aggressive primary brain tumor with a poor prognosis and median overall survival of approximately 12-15 months.^1,2 Despite the advancements in treatment, GBM remains difficult to treat and its poor prognosis is attributed to its invasive nature and resistance mechanisms such as dysregulated cell division, cell migration, invasion, tumor heterogeneity, and the blood brain barrier.² GBM progression has been linked to dysregulation of multiple signaling pathways, notably constitutively activated Signal Transducer and Activator of Transcription 3 (STAT3).³ STAT3 promotes tumor cell survival, proliferation, invasion, and immune evasion, and its activation is associated with poorer outcomes in GBM.³ Tumor Treating Fields (TTF) is a novel, FDA-approved, non-invasive adjunctive therapy that delivers low-intensity, alternating electric fields via transducer arrays placed on the scalp.⁴ While the mechanisms of action of TTF were primarily understood to be antimitotic, they remain poorly understood with recent studies suggesting TTF may also downregulate the STAT3 pathway and induce autophagy via miR-29b/Akt2.^4-8

Objectives: This review aims to explore the multifaceted mechanisms by which TTF exerts its anti-tumor effects in GBM and evaluate its potential synergistic role alongside existing therapies.

Search Methods: An online search in the PubMed database was conducted from 2018 to 2025 using the following keywords: “glioblastoma”, “tumor treating fields”, “STAT3”, and “autophagy”.

Results: TTF suppress GBM growth by inducing autophagy through downregulation of Akt2 via miR-29b upregulation and increasing autophagy-related proteins Beclin1, LC3, and Atg5.⁵ Additionally, TTF therapy demonstrates synergistic effects when combined with other therapies such as Sorafenib and Hyperthermia Therapy (HT).^6,7 These combined therapeutic strategies suppress STAT3 activation which reduced cell migration, invasion, and increased cancer cell apoptosis.^6,7 The SPARE clinical trial further established TTF’s safety, tolerability, and potential clinical benefit.⁸ It achieved a median progression-free survival of 6.9 months in a predominantly unmethylated promoter patient cohort, a chemoresistant group that is difficult to treat.⁸

Conclusion: TTF is a promising adjunctive therapy for GBM, working through multifaceted mechanisms that address key barriers in GBM management. It reduces cell proliferation and invasion in GBM by inducing autophagy via miR-29b mediated Akt2 suppression and inhibiting the STAT3 pathway.^5-7 When TTF therapy is combined with other treatment methods such as Sorafenib and HT, these effects are enhanced, particularly through greater suppression of STAT3 activity, leading to reduced tumor progression and invasiveness.^6,7 The findings from the SPARE clinical trial reinforced the safety, tolerability, and efficacy of TTF in a patient group with typically resistant disease profiles.⁸ Further studies are warranted to optimize combination strategies and fully elucidate the long-term clinical benefits of TTF-based therapy.

Works Cited:

1. McKinnon C, Nandhabalan M, Murray SA, Plaha P. Glioblastoma: Clinical presentation, diagnosis, and Management. BMJ. Published online July 14, 2021. doi:10.1136/bmj.n1560
2. Dewdney B, Jenkins MR, Best SA, et al. From signalling pathways to targeted therapies: Unravelling glioblastoma’s secrets and harnessing two decades of progress. Signal Transduction and Targeted Therapy. 2023;8(1). doi:10.1038/s41392-023-01637-8
3. Ganguly D, Fan M, Yang CH, et al. The critical role that STAT3 plays in glioma-initiating cells: STAT3 addiction in glioma. Oncotarget. 2018;9(31):22095-22112. doi:10.18632/oncotarget.25188
4. Moser JC, Salvador E, Deniz K, et al. The mechanisms of action of tumor treating fields. Cancer Research. 2022;82(20):3650-3658. doi:10.1158/0008-5472.can-22-0887
5. Kim EH, Jo Y, Sai S, et al. Tumor-treating fields induce autophagy by blocking the akt2/MIR29B axis in glioblastoma cells. Oncogene. 2019;38(39):6630-6646. doi:10.1038/s41388-019-0882-7
6. Kim JY, Jo Y, Oh HK, Kim EH. Sorafenib increases tumor treating fields-induced cell death in glioblastoma by inhibiting STAT3. Am J Cancer Res. 2020;10(10):3475-3486. Accessed March 13, 2025. https://e-century.us/files/ajcr/10/10/ajcr0119711.pdf
7. Jo Y, Han YI, Lee E, et al. The combination of tumor treating fields and hyperthermia has synergistic therapeutic effects in glioblastoma cells by downregulating STAT3. Am J Cancer Res. 2022;12(3):1423-1432. Accessed March 13, 2025. https://pmc.ncbi.nlm.nih.gov/articles/PMC8984886/pdf/ajcr0012-1423.pdf
8. Song A, Bar-Ad V, Martinez N, et al. Initial experience with scalp sparing radiation with concurrent temozolomide and tumor treatment fields (spare) for patients with newly diagnosed glioblastoma. Journal of Neuro-Oncology. 2020;147(3):653-661. doi:10.1007/s11060-020-03466-z