Liu Jing, Jiang Xiaomin, Li Youyou, Yang Kaiting, Weichselbaum Ralph R, Lin Wenbin
Department of Chemistry, University of Chicago, 929 East 57th Street, Chicago, Illinois 60637, United States.
Department of Radiation and Cellular Oncology and Ludwig Center for Metastasis Research, University of Chicago, 5758 South Maryland Avenue, Chicago, Illinois 60637, United States.
ACS Nano. 2024 Feb 13;18(6):5152-5166. doi: 10.1021/acsnano.3c12678. Epub 2024 Jan 29.
Blockade of programmed cell death-1/programmed cell death-ligand 1 (PD-L1) immune checkpoints with monoclonal antibodies has shown great promise for cancer treatment, but these antibodies can cause immune-related adverse events in normal organs. Here we report a dual-cell targeted chemo-immunotherapeutic nanoscale coordination polymer (NCP), OxPt/BP, comprising oxaliplatin (OxPt) and 2-bromopalmitic acid (BP), for effective downregulation of PD-L1 expression in both cancer cells and dendritic cells (DCs) by inhibiting palmitoyl acyltransferase DHHC3. OxPt/BP efficiently promotes DC maturation by increasing intracellular oxidative stress and enhancing OxPt-induced immunostimulatory immunogenic cancer cell death. Systemic administration of OxPt/BP reduces the growth of subcutaneous and orthotopic colorectal carcinoma by facilitating the infiltration and activation of cytotoxic T lymphocytes together with reducing the population of immunosuppressive regulatory T cells. As a result, OxPt/BP significantly extends mouse survival without causing side effects. This work highlights the potential of NCPs in simultaneously reprogramming cancer cells and DCs for potent cancer treatment.
用单克隆抗体阻断程序性细胞死亡蛋白1/程序性细胞死亡配体1（PD-L1）免疫检查点在癌症治疗方面已显示出巨大潜力，但这些抗体可在正常器官中引发免疫相关不良事件。在此，我们报告一种双细胞靶向化学免疫治疗纳米级配位聚合物（NCP），即奥沙利铂（OxPt）/2-溴棕榈酸（BP）组成的OxPt/BP，其通过抑制棕榈酰转移酶DHHC3有效下调癌细胞和树突状细胞（DC）中PD-L1的表达。OxPt/BP通过增加细胞内氧化应激并增强OxPt诱导的免疫刺激性免疫原性癌细胞死亡，有效促进DC成熟。全身给药OxPt/BP可通过促进细胞毒性T淋巴细胞的浸润和激活以及减少免疫抑制性调节性T细胞的数量，来降低皮下和原位结直肠癌的生长。结果，OxPt/BP显著延长小鼠生存期且不引起副作用。这项工作突出了NCP在同时重编程癌细胞和DC以进行有效癌症治疗方面的潜力。
