<p>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 Fe²⁺, 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 CaO₂ and the glutaminase inhibitor C968 onto mesoporous polydopamine nanocarriers. Under acidic condition, CaO₂ can generate O₂ and H₂O₂. The alleviation of hypoxia by the generated O₂ upregulates HMOX1 expression, which subsequently catalyzes heme degradation into Fe²⁺ while simultaneously downregulating the iron exporter SLC40A1. This dual action disrupts iron homeostasis and promotes intracellular Fe²⁺ accumulation. The accumulated Fe²⁺ reacts with H₂O₂ 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.</p>