Nanoengineered T cell membrane-coated nanodecoys blocking LAG-3/FGL1 to enhance cancer immunotherapy

Immune checkpoint blockade resistance, driven by alternative immune checkpoint upregulation and inefficient T cell-mediated immune stimulation, remains a major challenge in cancer immunotherapy. Here, we present a nanoengineered T cell membrane-coated nanodecoy (NTND) that effectively disrupts the interaction between FGL1-LAG-3, thereby alleviating immunosuppressive signaling and restoring T cell-mediated antitumor immunity. The NTNDs integrate a T cell membrane with high LAG-3 expression and pH-sensitive liposomes sonosensitizer encapsulating the sonosensitizer hematoporphyrin monomethyl ether (HMME). Within the tumor microenvironment (TME), the NTNDs gradually disintegrated and released the immune checkpoint molecules LAG-3 from T cell membrane, which can competitively bind to FGL1 on tumor cells, thereby relieving the immune suppressive effects. Additionally, the generation of abundant reactive oxygen species (ROS) under ultrasound irradiation induces immunogenic cell death (ICD), thereby promoting dendritic cell maturation and cytotoxic T cell infiltration to amplify anti-PD-1 efficacy. Our findings demonstrate that NTNDs can effectively restore the ability of T cells to eliminate anti-PD-1-resistant tumors, suggesting a promising strategy for overcoming immunoresistance in cancer treatment.