A Mutually Reinforcing Nanoplatform Orchestrates Immunogenic Ferroptosis and Reprogramming of Tumor-Associated Macrophages for Potent Immunotherapy.

Solid tumors present formidable barriers to immunotherapy due to low immunogenicity and a highly suppressive microenvironment. This study introduces Hb-DD@SRF, a mutually reinforcing nanoplatform comprising a sorafenib (SRF)-loaded core coated with a dual-targeting hemoglobin (Hb) shell. Upon targeting iron transporters on tumor cells, Fe derived from Hb catalyzes reactive oxygen species (ROS) generation, while acidic conditions trigger SRF release to inhibit glutathione peroxidase 4 (GPX4), synergistically amplifying ferroptosis. This robust process elicits immunogenic cell death to prime T cells. Crucially, Hb-mediated oxygenation precisely offsets the severe hypoxia resulting from SRF, establishing a complementary loop that prevents drug resistance. Furthermore, the platform targets M2 macrophages via the haptoglobin pathway, where oxygen and SRF jointly reprogram them to reverse immunosuppression. This remodeled immunostimulatory microenvironment synergizes with anti-PD-L1 therapy to achieve pronounced suppression of primary and metastatic tumors. Collectively, Hb-DD@SRF orchestrates ferroptosis amplification and comprehensive microenvironment modulation to potentiate antitumor immunotherapy.