肿瘤微环境
免疫疗法
癌症研究
癌症免疫疗法
CD8型
免疫系统
黑色素瘤
医学
T细胞
透明质酸
癌症
免疫学
内科学
解剖
作者
Huapan Fang,Yi‐Cheng Daniel Wu,Linfu Chen,Zhiqin Cao,Zheng Deng,Rui Zhao,Lin Zhang,Yang Yang,Zhuang Liu,Qian Chen
出处
期刊:ACS Nano
[American Chemical Society]
日期:2023-02-21
卷期号:17 (5): 4748-4763
被引量:5
标识
DOI:10.1021/acsnano.2c11159
摘要
Obesity usually induces systemic metabolic disturbances, including in the tumor microenvironment (TME). This is because adaptive metabolism related to obesity in the TME with a low level of prolyl hydroxylase-3 (PHD3) depletes the major fatty acid fuels of CD8+ T cells and leads to the poor infiltration and unsatisfactory function of CD8+ T cells. Herein, we discovered that obesity could aggravate the immunosuppressive TME and weaken CD8+ T cell-mediated tumor cell killing. We have thus developed gene therapy to relieve the obesity-related TME to promote cancer immunotherapy. An efficient gene carrier was prepared by modifying polyethylenimine with p-methylbenzenesulfonyl (abbreviated as PEI-Tos) together with hyaluronic acid (HA) shielding, achieving excellent gene transfection in tumors after intravenous administration. HA/PEI-Tos/pDNA (HPD) containing the plasmid encoding PHD3 (pPHD3) can effectively upregulate the expression of PHD3 in tumor tissues, revising the immunosuppressive TME and significantly increasing the infiltration of CD8+ T cells, thereby improving the responsiveness of immune checkpoint antibody-mediated immunotherapy. Efficient therapeutic efficacy was achieved using HPD together with αPD-1 in colorectal tumor and melanoma-bearing obese mice. This work provides an effective strategy to improve immunotherapy of tumors in obese mice, which may provide a useful reference for the immunotherapy of obesity-related cancer in the clinic.
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