Multiomics Insights into the Mechanism and Enhanced Efficacy of Tumor Treating Fields (TTFields) Therapy in Glioblastoma

Glioma is an aggressive brain tumor that requires challenging
treatments.
Tumor Treating Fields (TTFields), an FDA-approved therapy for glioblastoma
(GBM), pleural mesothelioma, and platinum-refractory metastatic nonsmall
cell lung cancer (in combination with PD-1/PD-L1 inhibitors or docetaxel),
employs specific frequency electric fields to disrupt cell division
and enhance treatment efficacy. However, their molecular mechanisms
remain unclear. This study aimed to elucidate these mechanisms and
optimize the therapeutic potential of TTFields through quantitative
proteomics, phosphoproteomics, and glycoproteomics. Pathway analysis
of the proteomics revealed that TTFields impact the cell cycle, DNA
repair, autophagy, and DNA replication. Phosphoproteomic studies further
demonstrated a marked decline in the activity of key kinases ABL1
and PDK1, while glycoproteomics highlighted disruptions in cell adhesion
and ECM-receptor interactions. Notably, proteomic analysis identified
an upregulation of PARP1 and BRD4 protein levels, suggesting a previously
unrecognized resistance mechanism. Consistently, combining TTFields
with inhibitors targeting these proteins significantly enhanced the
treatment efficacy in U87 cells. Thus, this study uncovers comprehensive
molecular mechanisms underlying TTFields’ effects on GBM cells
and supports the development of concomitant therapies to enhance treatment
efficacy.

胶质瘤（Glioma）是一种侵袭性极强的脑肿瘤，临床治疗极具挑战。肿瘤治疗电场（Tumor Treating Fields，TTFields）是经美国食品药品监督管理局（FDA）批准的疗法，可用于胶质母细胞瘤（glioblastoma，GBM）、胸膜间皮瘤，以及铂类难治性转移性非小细胞肺癌（需联合PD-1/PD-L1抑制剂或多西他赛），其通过施加特定频率的电场干扰细胞分裂，进而提升治疗效果，但该疗法的分子机制尚未明确。本研究旨在阐明TTFields的作用机制，并通过定量蛋白质组学、磷酸化蛋白质组学及糖蛋白质组学优化其治疗潜力。蛋白质组学通路分析显示，TTFields可影响细胞周期、DNA修复、自噬及DNA复制过程。磷酸化蛋白质组学研究进一步证实，关键激酶ABL1与PDK1的活性显著降低；而糖蛋白质组学则揭示了细胞黏附与细胞外基质（Extracellular Matrix，ECM）-受体互作的紊乱。值得关注的是，蛋白质组学分析发现PARP1与BRD4的蛋白水平上调，这提示了一种此前未被发现的耐药机制。后续实验验证表明，将TTFields与靶向这两种蛋白的抑制剂联合使用，可显著提升U87细胞的治疗效果。综上，本研究全面揭示了TTFields作用于胶质母细胞瘤细胞的分子机制，为开发联合疗法以增强治疗疗效提供了理论依据。