Intermittent fasting inhibits Tp53-driven glioma through gut microbiota-mediated methionine-m⁶A regulation

Intermittent fasting (IF) has emerged as a potential cancer treatment modality, although its tumor-suppressive effects are limited. Glioblastoma (GBM) can be classified into CDKN2A subtype and TP53 subtype. Here, we discover that the efficacy of IF is correlated with tumor subtypes of GBM. IF significantly inhibite GBM progression in mice with the Tp53 GBM model, whereas its inhibitory effect is not significant in the Cdkn2a GBM model. Multi-omics sequencing is performed in the IF-responsive Tp53 GBM mouse model, delineating a comprehensive molecular profiling of IF that including the spatial transcriptome, spatial metabolome, single-cell transcriptome, single-cell RNA methylation, metabolome, and microbiome. Through systematic biological analysis and rescue experiments conducted in IF-responsive Tp53 GBM mice model, we demonstrate that the efficacy of IF is primarily mediated by alterations in the gut microbiota, which subsequently modulate the production of the microbial metabolite methionine sulfoxide. Methionine sulfoxide, by regulating m⁶A modification, inhibits the TGF-β signaling pathway, resulting in suppressing GBM progression. This study proposes a genotype-based hypothesis for the therapeutic effects of IF on tumors, and elucidates the potential RNA modification-related molecular mechanisms underlying the effective suppression of GBM by IF.