An endoplasmic reticulum-enriched nanogel couples ferroptotic tumor damage with macrophage reprogramming for triple-negative breast cancer immunotherapy

Abstract

Triple-negative breast cancer (TNBC) is characterized by severely immunosuppressive tumor microenvironment (TME), which leads to tumor ferroptosis resistance and dominant protumor M2 macrophages, restraining innate-to-adaptive antitumor immune cascade. Herein, an endoplasmic reticulum (ER)-enriched pH/redox-sensitive SPIONS@P-CpG-DOX nanogel was constructed to realize dual ER-targeted manipulation on TNBC cells and tumor-associated macrophages (TAMs) to elicit an ER-centered innate-to-adaptive immune amplification axis. In TNBC cells, nanogel-induced ER stress inhibits the GSH-GPX4 axis and accelerates lipid peroxidation, triggering ER-originated ferroptosis and immunogenic cell death (ICD) to release antigens and damage-associated molecular patterns (DAMPs) for immune priming. In macrophages, nanogel activates ER-dependent STING/NF-κB pathways without ferroptosis, facilitating M2-to-M1 polarization and inflammatory TME remodeling. The dual ER-initiated pathways synergistically facilitate dendritic cell (DC) maturation, enhance intratumoral CD4+ and CD8+ T-cell infiltration and build long-term systemic immune memory. In 4T1 TNBC models, the nanogel efficiently inhibits primary tumor growth, postoperative recurrence, distant rechallenge and lung metastasis with favorable biosafety. This work validates ER as a core regulatory hub linking tumor ferroptosis and macrophage reprogramming, providing an organelle-targeted strategy for durable TNBC immunotherapy.