Intratumoral Fusobacterium nucleatum promotes ferroptosis resistance and a disulfide-stress-associated vulnerability under glucose restriction.

Fusobacterium nucleatum (Fn) is an intracellular oncogenic bacterium implicated in multiple cancers. Although Fn has been linked to resistance to anticancer therapies, its effects on therapies targeting metabolic cell-death programs remain unclear. Here, we show that intratumoral Fn abundance is positively associated with SLC7A11 expression and that Fn infection attenuates Era- and RSL3-induced ferroptosis in tumor cells. Live-versus-killed, donor-based, and pharmacological evidence suggests that H2S generated during Fn infection contributes to SLC7A11 induction and engagement of the downstream GSH/GPX4 axis. Fn infection also reduces lipid-peroxide and Fe2⁺ accumulation and is accompanied by ACSL4 downregulation and FTH1 upregulation. Fn-infected cells display increased glucose uptake and a heightened dependence on glucose. Under glucose-replete conditions, Fn-infected cells are relatively resistant to ferroptosis, whereas glucose deprivation exposes a conditional vulnerability accompanied by disulfide stress. RSL3 further sensitized Fn-infected cells to glucose restriction, and combined GPX4 inhibition with the GLUT1 inhibitor BAY876 enhanced antitumor activity in Fn-infected solid-tumor models. These findings identify a nutrient-dependent metabolic liability associated with Fn infection and support further evaluation of combined glucose-transport and GPX4 inhibition in appropriately controlled models.