Inducing ferroptotic cell death has been recognized as a promising approach in cancer therapy. However, ferroptosis can provoke tumor infiltration by myeloid-derived suppressor cells (MDSCs) through HMGB1 secretion, causing a tumor suppressive immune response. On the other hand, ferroptosis also occurs the immune cells due to its non-selective properties, which can compromise anti-tumor immunity. To address these challenges, a two-pronged approach is proposed, encompassing selectively triggered ferroptosis in tumor cells and HMGB1 blockade, aimed at eliciting systemic anti-tumor immunity and alleviating immunosuppression. Herein, GSH-specific driven nanoplatform is composed of uniform FeOOH nanospindles coated with tetrasulfide bond-bridged mesoporous organosilica (DMOS) shell, and loaded with the HMGB1 inhibitor, glycyrrhizic acid (GA). This nanoplatform is endowed with high glutathione (GSH) depletion efficiency and exhibits highly efficient Fe