The TFDP2-PDK3 axis drives glucose metabolic reprogramming to promote radioresistance in nasopharyngeal carcinoma.

Abstract

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. 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. 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. 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.