Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology · 2026
The TFDP2-PDK3 axis drives glucose metabolic reprogramming to promote radioresistance in nasopharyngeal carcinoma.
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Yang Qi, Fang Jianbo, Chen Cuiying, Zhang Chunyan, Hu Shulu, Lv Qiong, Li Xuechun, Liu Xiang, Meng Hui, Shen Weitao, Zhang Jian
Аннотация
BACKGROUND: Although nasopharyngeal carcinoma (NPC) is highly radiosensitive, tumor radioresistance inevitably leads to local recurrence and distant metastasis, posing a major clinical challenge for NPC treatment.
MATERIALS AND METHODS: By integrating single-cell RNA sequencing data from eight local NPC samples, mRNA sequencing data from pre-established radioresistant cell models, and phenotype-associated gene sets shared across heterogeneous tumor cells, we identified the potential central role of Transcription Factor Dimerization Partner 2 (TFDP2) in radioresistance. After demonstrating the critical role of TFDP2 in radioresistance through comprehensive in vitro and in vivo experiments, we performed transcriptome sequencing on TFDP2-silenced cells and conducted bioinformatic analysis to explore the potential mechanism. Finally, using a series of functional assays, including examination of key metabolic indicators, immunofluorescence, immunohistochemistry, chromatin immunoprecipitation (ChIP)-qPCR, and dual-luciferase reporter assays, we elucidated the precise molecular mechanism by which TFDP2 mediates radioresistance.
RESULTS: TFDP2 plays a pivotal role in the process of radioresistance in NPC: its elevated expression not only enhances radiation resistance but also predicts worse clinical outcomes in publicly available NPC cohorts. Mechanistically, TFDP2 promotes radioresistance by activating Pyruvate Dehydrogenase Kinase Isozyme 3 (PDK3) transcription, which reprograms metabolism from oxidative phosphorylation to glycolysis.
CONCLUSIONS: This work establishes TFDP2-mediated metabolic reprogramming as a critical mechanism of radioresistance, offering mechanistic insights and a potential therapeutic target for improving radiotherapy outcomes in NPC.
MATERIALS AND METHODS: By integrating single-cell RNA sequencing data from eight local NPC samples, mRNA sequencing data from pre-established radioresistant cell models, and phenotype-associated gene sets shared across heterogeneous tumor cells, we identified the potential central role of Transcription Factor Dimerization Partner 2 (TFDP2) in radioresistance. After demonstrating the critical role of TFDP2 in radioresistance through comprehensive in vitro and in vivo experiments, we performed transcriptome sequencing on TFDP2-silenced cells and conducted bioinformatic analysis to explore the potential mechanism. Finally, using a series of functional assays, including examination of key metabolic indicators, immunofluorescence, immunohistochemistry, chromatin immunoprecipitation (ChIP)-qPCR, and dual-luciferase reporter assays, we elucidated the precise molecular mechanism by which TFDP2 mediates radioresistance.
RESULTS: TFDP2 plays a pivotal role in the process of radioresistance in NPC: its elevated expression not only enhances radiation resistance but also predicts worse clinical outcomes in publicly available NPC cohorts. Mechanistically, TFDP2 promotes radioresistance by activating Pyruvate Dehydrogenase Kinase Isozyme 3 (PDK3) transcription, which reprograms metabolism from oxidative phosphorylation to glycolysis.
CONCLUSIONS: This work establishes TFDP2-mediated metabolic reprogramming as a critical mechanism of radioresistance, offering mechanistic insights and a potential therapeutic target for improving radiotherapy outcomes in NPC.