Reprogramming the Tumor Microenvironment through Second‐Near‐Infrared‐Window Photothermal Genome Editing of PD‐L1 Mediated by Supramolecular Gold Nanorods for Enhanced Cancer Immunotherapy

Abstract A photothermal genome‐editing strategy is described to improve immune checkpoint blockade (ICB) therapy by CRISPR/Cas9‐mediated disruption of PD‐L1 and mild‐hyperthermia‐induced activation of immunogenic cell death (ICD). This strategy relies on a supramolecular cationic gold nanorod that not only serves as a carrier to deliver CRISPR/Cas9 targeting PD‐L1 , but also harvests the second near‐infrared‐window (NIR‐II) light and converts into mild hyperthermia to induce both ICD and gene expression of Cas9. The genomic disruption of PD‐L1 significantly augments ICB therapy by improving the conversion of dendritic cells to T cells, followed by promoting the infiltration of cytotoxic T lymphocytes into tumors, thereby reprogramming immunosuppressive tumor microenvironment into immunoactive one. Such a therapeutic modality greatly inhibits the activity of primary and metastatic tumors and exhibits long‐term immune memory effects against both rechallenged and recurrent tumors. The current therapeutic strategy for synergistic PD‐L1 disruption and ICD activation represents an appealing way for cancer immunotherapy.