Division of Biliary Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.
Research Center for Biliary Diseases, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.
ACS Appl Mater Interfaces. 2024 Sep 4;16(35):45901-45916. doi: 10.1021/acsami.4c06833. Epub 2024 Aug 21.
Immune checkpoint blockade (ICB) therapy, while showing promise in various cancers, exhibits limited effectiveness in hepatic carcinoma due to the tumor's immunosuppressive microenvironment (TME) and challenges associated with immune cell infiltration. Efforts to transform the "cold" TME into an "inflamed" state, notably through chemo-immunotherapy, have sparked interest due to their potential to induce immunogenic cell death and augment the infiltration of cytotoxic T lymphocytes (CTLs). Nonetheless, the efficacy of chemo-immunotherapy is often compromised by suboptimal pharmacokinetics, poor tumor accumulation, and off-target toxicity. Herein, in response, we introduce an innovative, milder thermal therapeutic approach leveraging gold nano frameworks with mesopores for the targeted delivery of the immunostimulant imiquimod and NIR-II photothermal therapy. This strategy employs targeted molecule modifications to ensure precise tumor targeting, guided by photoacoustic imaging. Subsequent to mild thermal treatment, there is a release of immunogenic proteins (CRT and HSP90), enhancing tumor immunogenicity. Assisted by imiquimod, substantial CTL infiltration occurs, accompanied by pro-inflammatory factor release (TNF-α, IL-6), transforming M2 macrophages into the M1 phenotype. Ultimately, the proposed strategy combines PD-L1/PD-1 blockade, imiquimod and mild thermal treatment to synergistically enhance tumor immunogenicity, remodel the TME, and restrain hepatic carcinoma, making strides in ICB synergistic immune-thermal therapy.
免疫检查点阻断(ICB)疗法在各种癌症中显示出前景,但由于肿瘤的免疫抑制微环境(TME)和免疫细胞浸润相关的挑战,在肝癌中的效果有限。为了将“冷”TME转化为“炎症”状态,特别是通过化疗-免疫治疗,人们对此产生了兴趣,因为它们有可能诱导免疫原性细胞死亡并增加细胞毒性 T 淋巴细胞(CTL)的浸润。然而,化疗-免疫治疗的疗效常常因药代动力学不佳、肿瘤积累不良和脱靶毒性而受到影响。在此,我们引入了一种创新的、温和的热治疗方法,利用具有介孔的金纳米框架来靶向递送电免疫刺激剂咪喹莫特和近红外-II 光热治疗。该策略通过光声成像,利用靶向分子修饰来确保精确的肿瘤靶向。在温和的热治疗后,会释放出免疫原性蛋白(CRT 和 HSP90),增强肿瘤的免疫原性。在咪喹莫特的辅助下,大量 CTL 浸润,并伴有促炎因子的释放(TNF-α、IL-6),将 M2 巨噬细胞转化为 M1 表型。最终,该策略结合了 PD-L1/PD-1 阻断、咪喹莫特和温和的热治疗,以协同增强肿瘤免疫原性、重塑 TME 和抑制肝癌,在 ICB 协同免疫-热治疗方面取得了进展。