Nanodrug combining chemotherapy and ferroptosis mediated cGAS-STING activation for potent antitumor immunity

Abstract

Triple-negative breast cancer (TNBC) presents a significant challenge in treatment due to its aggressive and immunosuppressive tumor microenvironment (TME). In this study, we developed a nanodrug, DFTNPs, which combined doxorubicin (DOX) and Fe³⁺–tannic acid (TA) to synergistically induce immunogenic cell death (ICD) and activate the cGAS-STING pathway. DFTNPs efficiently accumulated in tumors through the enhanced permeability and retention (EPR) effect, releasing DOX and Fe³⁺ in the weakly acidic and GSH-rich TME. The release of DOX acted on the DNA of cancer cells and induced tumor cell death, while the liberation of Fe³⁺ triggered ferroptosis characterized by lipid peroxidation (LPO). Experimental results demonstrated that DFTNPs induced ICD and activated the cGAS-STING pathway, triggering a robust antitumor immune response that promoted dendritic cell (DC) maturation. In vivo studies revealed that DFTNPs treatment significantly suppressed tumor growth, exhibited excellent biocompatibility, and increased infiltration of CD4⁺ and CD8⁺ T lymphocytes. In conclusion, DFTNPs integrated chemotherapy, ferroptosis and immunotherapy to counteract the immunosuppressive TME effectively, presenting a promising therapeutic strategy for TNBC.