Nanoparticle‐mediated HMGA1 Silencing Promotes Lymphocyte Infiltration and Boosts Checkpoint Blockade Immunotherapy for Cancer

Abstract For most cancer types, only a minority of cancer patients respond to checkpoint inhibition therapy. T lymphocyte infiltration is critically important for checkpoint blockade immunotherapy. High expression of high mobility group protein A1 (HMGA1) is observed in rapidly proliferating neoplastic cells, and is reported to contribute to the immunosuppressive microenvironment in the tumor. Herein, whether the silencing of HMGA1 using a nanoparticle (NP) approach could promote T lymphocyte infiltration into the tumor, and sensitize tumors to checkpoint inhibitor therapy in several orthotopic murine cancer models, which has high levels of HMGA1 but little T lymphocyte infiltration, is investigated. Selectively silencing HMGA1 using a lipid‐protamine‐hyaluronic acid‐siHMGA1 (LPH‐siHMGA1) NP system greatly enhances the lymphocyte infiltration in the tumor. Furthermore, the combination of LPH‐siHMGA1 and a locally expressed PD‐L1 inhibitor system, a lipid‐protamine‐DNA NP loaded with plasmid encoding the PD‐L1 trap fusion protein, significantly inhibits the tumor growth and prolonged survival. LPH‐siHMGA1 also decreased the content of stem cells in the tumor. These findings highlight the potential of targeting HMGA1, especially using a nano approach, in the combination with cancer immunotherapy, and provide a strategy for broadening the application and enhancing the efficacy of checkpoint inhibitors.