Glutathione‐Depletable Nanoinducer for Boosting Immunomodulatory Synergistic Therapy to Reverse Breast Cancer Chemoresistance

M2-type tumor-associated macrophage (TAM)-dominated immunosuppressive tumor microenvironment (TME) often contributes to chemoresistance. For the first time, a glutathione (GSH)-responsive metal-organic framework (MOF) nanoinducer is engineered for co-delivering doxorubicin (DOX) and HIF-1α antisense oligonucleotide labeled with Ce6 photosensitizer. This new crystal structure exhibited robust stability in simulated physiological environments. Furthermore, multimodal synergistic effects are exhibited upon tumor cell internalization with the nanoinducer. GSH depletion synergizes with photodynamic therapy (PDT) generated reactive oxygen species (ROS) to induce ferroptosis, which effectively drives phenotypic reprogramming of M2-TAMs toward M1 macrophages. HIF-1α antisense oligonucleotides downregulate HIF-1α expression as well as downstream P-glycoprotein (P-gp) mediated drug efflux, thereby significantly enhancing DOX accumulation in chemoresistant breast cancer cells. Consequently, the combination of DOX with ferroptosis-induced immunogenic cell death (ICD) initiates antitumor immunity and activates cytotoxic T lymphocytes. This smart biomimetic nanoinducer demonstrates robust antitumor performance in both in vitro and in vivo models, effectively activating tumor-specific immune responses. A promising candidate nanodrug with a new crystal structure is presented for chemotherapy-immunotherapy combination therapy.