Hypoxia nanoalleviator with dual disruption of iron and redox metabolism for efficient ferroptosis-mediated cancer immunotherapy

Ferroptosis-based cancer immunotherapy is often limited by insufficient intracellular iron and inherent antioxidant defense. Inspired by heme oxygenase 1 (HMOX1), which catalyzes heme to release endogenous Fe 2+ , and informed by bioinformatics hints indicating a potential correlation between hypoxia-inducible factor-1α (HIF-1α) and HMOX1, as well as the critical role of glutaminase activity in redox metabolism. We rationally designed a hypoxia nanoalleviator (MPCC) co-loaded CaO 2 and the glutaminase inhibitor C968 onto mesoporous polydopamine nanocarriers. Under acidic condition, CaO 2 can generate O 2 and H 2 O 2 . The alleviation of hypoxia by the generated O₂ upregulates HMOX1 expression, which subsequently catalyzes heme degradation into Fe 2+ while simultaneously downregulating the iron exporter SLC40A1. This dual action disrupts iron homeostasis and promotes intracellular Fe 2+ accumulation. The accumulated Fe 2+ reacts with H 2 O 2 via a Fenton-like reaction, producing ROS to induce ferroptosis. Concurrently, hypoxia alleviation reduces HIF-1α expression, and thereby inhibiting glutamate transporter SLC1A1 expression, combining with glutaminase inhibitor C968, dual suppressing glutathione production to disrupt redox metabolism, causing ROS storms, thereby robustly enhancing ferroptosis. Enhanced ferroptosis effectively triggers immunogenic cell death, thereby activating T-cell immune responses and potently suppressing tumor growth and metastasis.