Leucine restriction ameliorates Fusobacterium nucleatum-driven malignant progression and radioresistance in nasopharyngeal carcinoma.

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.