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

Area of Science:

• Neuro-oncology
• Cancer immunology
• Biophysics

Background:

• Glioblastoma (GBM) has a poor prognosis despite standard treatments.
• Tumor Treating Fields (TTFields) improve survival but have complex TME interactions.
• Understanding TTFields' TME effects is crucial for optimizing GBM therapy.

Purpose of the Study:

• To review the mechanistic interactions between TTFields and the GBM TME.
• To explore the convergence of TTFields and radiotherapy in GBM treatment.
• To propose strategies for combining TTFields and radiotherapy.

Main Methods:

• Integrated mechanistic analysis of preclinical and clinical data.
• Focus on TTFields' effects on immune pathways, cell death, and GBM components.
• Examination of TTFields-radiotherapy combination mechanisms.

Main Results:

• TTFields activate innate immunity (cGAS/STING, AIM2), induce immunogenic cell death, and reprogram macrophages.
• TTFields affect glioma stem cells, BBB permeability, invasion, angiogenesis, and autophagy.
• Convergent mechanisms with radiotherapy include DNA repair impairment and immune activation.

Conclusions:

• TTFields remodel the GBM TME and enhance immune responses.
• Combining TTFields with radiotherapy offers synergistic benefits.
• Further research should focus on optimal timing, hypofractionation, and biomarkers for TTFields-radiotherapy combinations.