Leucine restriction ameliorates Fusobacterium nucleatum-driven malignant progression and radioresistance in nasopharyngeal carcinoma
Songhe Guo, Shan Xing, Zhenyu Wu, Fangfang Chen, Xiaoyun Pan, Qifan Li, Wanli Liu, Ge Zhang
Abstract
Radiotherapy resistance is the main cause of treatment failure among patients with nasopharyngeal carcinoma (NPC). Recently, increasing evidence has linked the presence of intratumoral Fusobacterium nucleatum (Fn) with the malignant progression and therapeutic resistance of multiple tumor types, but its influence on NPC has remained largely unknown. We found that Fn is prevalent in the tumor tissue of patients with NPC and is associated with radioresistance. Fn invaded and proliferated inside NPC cells and aggravated tumor progression. Mechanistically, Fn slowed mitochondrial dysfunction by promoting mitochondrial fusion and decreasing ROS generation, preventing radiation-induced oxidative damage. Fn inhibited PANoptosis by the SLC7A5/leucine-mTORC1 axis during irradiation stress, thus promoting radioresistance. Treatment with the mitochondria-targeted antibiotics or dietary restriction of leucine reduced intratumoral Fn load, resensitizing tumors to radiotherapy in vivo . These findings demonstrate that Fn has the potential to be a predictive marker for radioresistance and to help guide individualized treatment for patients with NPC. • High abundance of F. nucleatum associated with poor radiotherapy efficacy in NPC • F. nucleatum proliferates in NPC cells and promotes tumor growth and metastasis • F. nucleatum promotes NPC radioresistance via the SLC7A5/leucine-mTORC1 axis • Leucine-restricted diet ameliorates radioresistance in NPC Guo et al. report that F . nucleatum drives radioresistance in nasopharyngeal carcinoma by reducing PANoptosis via the SLC7A5/leucine-mTORC1 axis. These findings reveal a mechanism of host-microbe interactions in nasopharyngeal carcinoma and potential strategies for improving clinical response to radiotherapy.