Photothermal therapy mediated by gold nanocages composed of anti-PDL1 and galunisertib for improved synergistic immunotherapy in colorectal cancer
Siyu Wang, Yue Song, Kunxia Cao, Lingxiao Zhang, Xuedong Fang, Fangfang Chen, Shouhua Feng, Fei Yan
Abstract
Colorectal cancer (CRC) is the second leading cause of cancer-related deaths worldwide. The primary treatment for CRC is surgical resection, along with chemotherapy in more advanced or inoperable cases. There is a growing interest to complement both curative and palliative treatment with immunotherapies such as the programmed cell death-1 (PD-1) and PD-ligand 1 (PDL1) checkpoint inhibitors and transforming growth factor (TGF) β inhibitors. However, the clinical outcomes of current immunotherapeutic strategies are limited by tumor heterogeneity and drug resistance. Nanomedicine-based photothermal therapy (PTT) has shown encouraging results for solid tumor ablation. Herein, we designed and synthesized gold nanocages functionalized with primary macrophage membrane and surface anti-PDL1 antibody, and loaded with a TGFβ inhibitor, galunisertib. The GNC-Gal@CMaP nanocomposites achieved low-temperature PTT and immunogenic cell death, which subsequently enhanced the anti-tumor efficacy of anti-PDL1 antibody and galunisertib via activation of antigen-presenting cells that primed tumor-specific effector T cells. This study provides experimental proof for a combination of immunotherapy and PTT against CRC. STATEMENT OF SIGNIFICANCE: The combination of photothermal therapy (PTT) with immunotherapy can achieve an inherently synergistic anti-tumor effect. Here we integrated low-temperature PTT, PDL1 antibody and TGF-β inhibitor in hollow gold nanocage nanocomposites (GNC-Gal@CMaP) that selectively targeted colon cancer cells and accumulated in the tumor microenvironment. The GNC-Gal@CMaP nanocomposites achieved low-temperature PTT and immunogenic cell death, which subsequently enhanced the anti-tumor efficacy of anti-PDL1 antibody and galunisertib via activation of antigen-presenting cells that primed tumor-specific effector T cells. This study provides experimental proof for a combination of immunotherapy and PTT against CRC.