Arginine nanoparticles mediated closed-loop ferroptosis enhancement for T cell activity boosting in cancer immunotherapy

Poor efficacy in solid tumor immunotherapy mainly ascribed to few CD8+ T cells infiltration with low activity in tumor immunosuppressive microenvironment (TIME). Ferroptosis can be harnessed for activating system immune response for more CD8+ T cells infiltration. However, the activity of infiltrated CD8+ T cells will be heavily weakened by the nutrient barrenness and immunosuppressive microenvironment, which formidably impaired the biologically closed-loop reciprocal process between active CD8+ T cells and cellular ferroptosis. Considering the above two key influence factors, we herein elaborately labeled L-Arginine (Arg) with 3,4-dihydroxybenzaldehyde (PA) via reversible Schiff-base bond, and then drive nanoassembly of PA-Argby iron ions mediation (Fe@PA-Arg NPs). Iron released from Fe@PA-Arg NPs in acidic tumor environment could produce reactive oxygen species (ROS) and thus successfully induce immunogenic ferroptosis of cancer cells. Subsequently, promoting the dendritic cells maturation and CD8+ T cells infiltration. Meanwhile, ROS could also induce the lipid peroxidation of tumor associated macrophages that contributed to mitochondrial dysfunction, thereby repolarized M2 to M1 phenotype to relieve the immunosuppression. Arg released from Fe@PA-Arg NPs as nutrient supply to restore infiltrated T cells' activity by combining Arg metabolic adaption with immunosuppressive mitigation. Reciprocally, restored activated CD8+ T cells could secrete high levels of Interferon-gamma, which in turn enhances ferroptosis, thereby successfully initiating and forming a closed-loop, and the tumor inhibition rate of 63.5% was achieved. This study highlights a novel and facile strategy to improve the immunotherapeutic efficiency of murine 4T1 solid tumors.