Lipid acid metabolism reprogramming nanoagent induces ferroptosis storm and cGAS-STING activation for metal-immunotherapy of triple negative breast cancer

• Lipid Acid Metabolism Reprogramming enhances αPD-L1 therapy effect. • Mn@SCD1i@αPD-L1 can lead to ferroptosis storm, cGAS-STING activation and Wnt/β-catenin pathway suppression. • Metal-immunotherapy induced by Mn@SCD1i@αPD-L1 can inhibit growth and metastasis of TNBC . Immune checkpoint inhibitor (ICI) therapy efficiency in triple negative breast cancer (TNBC) is restricted by the low immunogenicity in tumor microenvironment. Ferroptosis is a promising method to improve the hypoactive immune microenvironment. However, lipid acid metabolism abnormity of tumor microenvironment limited the ferroptosis and immune therapy effect. To address this dilemma, GSH responsive nanoparticles (Mn@SCD1i@αPD-L1) were designed by using Mn 3 O 4 as a carrier, linking SCD1 inhibitor (SCD1i, A939572) and immune checkpoint inhibitor (αPD-L1). Mn 2+ , SCD1i, and αPD-L1 were released into the tumor upon the stimulation of high GSH tumor microenvironment. Mn@SCD1i@αPD-L1 could amplify the ferroptosis induced by Mn 2+ through lipid acid metabolism regulation of decreasing monounsaturated fatty acids (MUFAs) synthesis. ROS/Lipid ROS storm provoked DNA damage, activating the cGAS-STING pathway. The damage-associated molecular patterns (DAMPs) generated by the ferroptosis and IFN-β released by the cGAS-STING pathway activation maturated the dendric cells (DCs) and then enhanced the CD8 + T cell infiltration in tumor microenvironment, promoting the effect of αPD-L1. Mn@SCD1i@αPD-L1 also intervened the Wnt/β-catenin pathway to promote the tumor cells to release CCL4, which recruits the DCs. What’s more, Mn 2+ -related T 1 magnetic resonance imaging was used to evaluate the real-time therapy efficiency. In summary, Mn@SCD1i@αPD-L1 efficiently enhances the αPD-L1 efficiency by ferroptosis and cGAS-STING pathway activation, providing a promising immunotherapy strategy for TNBC and other cold tumors.