A Bimetallic Nanomodulator to Reverse Immunosuppression via Sonodynamic‐Ferroptosis and Lactate Metabolism Modulation

Triple‐negative breast cancer (TNBC) responds poorly to immunotherapy due to insufficient immunogenicity and highly immunosuppressive tumor microenvironment (TME). Herein, an intelligent calcium/cobalt‐based nanomodulator (Ca,Co)CO3‐LND‐TCPP@F127‐TA (abbreviated as CCLT@FT) is developed to act as a sonodynamic‐ferroptosis inducer and metabolic immunoadjuvant to enhance anti‐tumor immunotherapy. More details, simultaneous reactive oxygen species (ROS) generation and glutathione (GSH) depletion can be achieved due to the existence of Co2+/Co3+ redox couple in CCLT@FT. Meanwhile, mitochondrial Ca2+ overload and tetrakis(4‐carboxyphenyl) porphyrin (TCPP)‐mediated sonodynamic therapy (SDT) further amplify the oxidative stress and promote ferroptosis in tumor cells. More impressively, CCLT@FT can modulate lactate metabolism by doping with cobalt and loading with lonidamine (LND, an inhibitor of MCT4), thereby reversing the high‐lactate immunosuppressive TME. Furthermore, the combination with immune checkpoint blockade (ICB) therapy is found to achieve superior anti‐tumor immunity, which in turn promotes ferroptosis of tumor cells by downregulating SLC7A11 protein, ultimately creating a “cycle” therapy. Overall, this work demonstrates a novel strategy for enhancing anti‐tumor immunotherapy based on a closed‐loop enhancement therapeutic route between CCLT@FT inducing ferroptosis/lactate metabolism modulation and ICB therapy, providing an alternative and important reference for effective immunotherapy of TNBC. A novel bimetallic nanomodulator (CCLT@FT) is constructed, which can serve as a SDT‐enhanced ferroptosis inducer and metabolic immunoadjuvant for TNBC concurrently to achieve regulation of the immunosuppressive TME and highly efficient anti‐tumor immunotherapy. More importantly, a closed‐loop enhancement therapeutic route between CCLT@FT inducing ferroptosis/lactate metabolism modulation and PD‐L1 immune checkpoint is achieved, exhibiting great promise.