Tumor Electric Field Therapy Inhibits TGF-β/C1R Signaling Axis-Driven Epithelial-Mesenchymal Transition in Glioblastoma - Original Article - open access

Sep 29, 2026

Glioblastoma (GBM) is an aggressive, treatment-resistant brain tumor, especially with a poor-prognosis mesenchymal subtype. Tumor electric field therapy (TEFT) is a promising adjunct, yet its molecular basis is unclear. Using CancerSEA functional-state analyses, TEFT-treated GBM models were evaluated for C1R roles via knockdown, assays of migration, invasion, proliferation, and pathway activity, followed by validation in animals and clinical specimens.

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Introduction

Tumor electric field therapy and clinical context

Rationale and overview of the study

CNS Neuroscience & Therapeutics | ORIGINAL ARTICLE OPEN ACCESS
Tumor Electric Field Therapy Inhibits TGF-β/C1R Signaling Axis-Driven Epithelial-Mesenchymal Transition in Glioblastoma
Junyi Chen1,2,3 | Yuyang Liu4,5 | Qi Liu1,6 | Hongyu Liu1,2 | Cheng Sun1,2 | Xu Chen1,2 | Xinchen Zhao1,2 | Jinxin Lan1,7 | Yaping Feng4 | Lilin Qin8 | Jialin Liu1,2 | Ze Li1,2 | Ling Chen1,2
1Medical School of Chinese PLA, Beijing, China | 2Department of Neurosurgery, Chinese PLA General Hospital, Beijing, China | 3Department of Neurosurgery, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China | 4Department of Neurosurgery, 920th Hospital of Joint Logistics Support Force, Kunming, China | 5Graduate School, Kunming Medical University, Kunming, China | 6Faculty of Hepato-Pancreato-Biliary Surgery, Chinese PLA General Hospital, Beijing, China | 7School of Medicine, Nankai University, Tianjin, China | 8Chongqing University Fuling Hospital, Chongqing, China
Correspondence: Ze Li ([lize301@163.com](lize301@163.com)) | Ling Chen ([chen_ling301@163.com](chen_ling301@163.com))
Received: 10 August 2025 | Revised: 30 November 2025 | Accepted: 19 December 2025
Keywords: complement C1R | EMT | glioblastoma | mesenchymal subtype | TGF-β signaling pathway | tumor electric field therapy | | --- | | ABSTRACT
Background: Glioblastoma (GBM) is one of the most aggressive and treatment-resistant primary brain tumors, with the mesenchymal subtype exhibiting particularly poor prognosis. Tumor electric field therapy (TEFT) has emerged as a promising adjunctive treatment, but its underlying molecular mechanisms remain incompletely understood.
Methods: GBM functional states were analyzed using CancerSEA datasets. GBM cell lines were treated with 200 kHz TEFTat 2.2 V/m for 72 h. C1R was knocked down using siRNA and shRNA. Cell morphology, migration, invasion, proliferation, and signaling pathways were assessed through various assays. Findings were validated in animal models and clinical specimens. Results: C1R was identified at the intersection of TEFT-downregulated genes, poor prognosis markers, and functional state genes. C1R was significantly upregulated in mesenchymal GBM and strongly correlated with epithelial-mesenchymal transition (EMT) . Single-cell RNA sequencing revealed C1R was predominantly expressed in MES-like malignant cells with high EMT signature scores. TEFT treatment induced morphological changes from elongated spindle-shaped to rounded epitheliallike morphology, increased E-cadherin expression, and decreased mesenchymal markers (N-cadherin, Vimentin, YKL-40) . Mechanistically, TEFT suppressed the TGF-β/SMAD2/3/STAT3 signaling pathway, downregulating C1R expression. C1Rknockdown significantly reduced tumor growth in vivo, while exogenous TGF-β restored C1R expression and reversed the mesenchymal phenotype in a dose-and time-dependent manner.
Conclusion: TEFT inhibits GBM progression by suppressing the TGF-β/SMAD2/3/STAT3/C1R axis, thereby attenuating EMT and reducing tumor aggressiveness. These findings uncover a novel mechanism of TEFT and identify C1R as a potential biomarker and therapeutic target for GBM. | | | | Abbreviations: CCK-8, cell counting kit-8; CGGA, Chinese Glioma Genome Atlas; DEGs, differentially expressed genes; DMEM, Dulbecco's modified Eagle medium; EdU, 5-ethynyl-2′-deoxyuridine; EMT, epithelial-mesenchymal transition; FBS, fetal bovine serum; GBM, glioblastoma; GTRD, Gene Transcription Regulation Database; HRQoL, health-related quality of life; IHC, immunohistochemistry; MES, mesenchymal; MET, mesenchymal-epithelial transition; NC, negative control; NCCN, National Comprehensive Cancer Network; PN, proneural; RPPA, reverse phase protein array; SD, standard deviation; ShRNA, short hairpin RNA; SiRNA, small interfering RNA; TCGA, The Cancer Genome Atlas; TEFT, tumor electric field therapy; TGF-β, transforming growth factor-beta; TISCH2, tumor immune single-cell Hub 2;

FAQs

What is the main problem addressed regarding glioblastoma?

Glioblastoma is highly aggressive, treatment-resistant, and often shows poor outcomes, particularly for the mesenchymal subtype.

How is tumor electric field therapy applied in the study context?

TEFT uses low-intensity, intermediate-frequency electric fields as a continuous postoperative/adjuvant approach, designed to interfere with tumor cell division and support other therapies.

What molecular axis does the study focus on?

The study centers on the TGF-β/SMAD2/3/STAT3 signaling axis and its regulation of C1R, linking this to epithelial-mesenchymal transition (EMT) and tumor progression.

Sep 29, 2026

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