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Dual-sensitization nanoformulation combining glutamine metabolism inhibition and Fas/FasL activation for enhanced colorectal cancer immunotherapy

文献类型：期刊论文

作者Yan, Dan3,4,5; Yi, Wenzhe3,5,7; Wu, Ting3,4,5; Hu, Shuangshuang3,5; Ding, Yan3,4,5; Qian, Xindi3,5; Zhao, Zhiwen3,5,7; Wang, Dangge1; Xu, Huae2,4; Cai, Ying3,5,6,7
刊名JOURNAL OF CONTROLLED RELEASE
出版日期2025-12-10
卷号388页码:14
关键词Glutamine inhibition Engineered immune cells Fas ligand Immunotherapy Colorectal cancer
ISSN号0168-3659
DOI10.1016/j.jconrel.2025.114324
英文摘要Altered glutamine metabolism in colorectal cancer (CRC) promotes immune evasion by inducing an immunosuppressive tumor microenvironment. Herein, we developed a nanocomplex by linking the anti-programmed death ligand 1 (PD-L1) antibody (alpha PDL1) with alanine-serine-cysteine transporter 2 antagonist V-9302 covalently via a glutathione-responsive linker (PVN). The PVN disintegrated and released V-9302, which suppresses glutamine uptake and upregulates the expression of PD-L1 and the Fas cell surface death receptor (Fas/CD95/ Apo-1) in tumor cells via the Ca2+/NF-kappa B signaling axis. This converted the PD-L1 elevation into therapeutic vulnerability, sensitizing tumor cells to immune checkpoint blockade. The upregulated tumor-associated Fas expression was utilized by Fas ligand (FasL)-overexpressing dendritic cell (FasL-DC) to activate death receptor pathways and induce Fas/FasL-mediated tumor apoptosis. The combination strategy termed PVN/FasL-DC, promoted dendritic cell maturation, epitope spreading, and increased the infiltration of CD8+ T cells, thereby enhancing antitumor efficacy. This study emphasizes the synergistic modulation of glutamine metabolism and death receptor pathways as a dual-sensitization strategy with promise for CRC immunotherapy.
WOS关键词TUMOR ; GLUTATHIONE ; RESISTANCE ; BLOCKADE ; CELLS
资助项目National Key Research and Development Program of China[2022YFC3401400] ; National Natural Science Foundation of China[32170935] ; National Natural Science Foundation of China[32561160090] ; National Natural Science Foundation of China[82373105] ; National Natural Science Foundation of China[32501236] ; Shanghai Sailing Program[24YF2755700] ; Shandong Laboratory Program[SYS202205] ; Key Research and Development Program of Jiangsu Province[BE2023834]
WOS研究方向Chemistry ; Pharmacology & Pharmacy
语种英语
WOS记录号WOS:001603127300002
出版者ELSEVIER
源URL[http://119.78.100.183/handle/2S10ELR8/319719]  
专题国家级研究中心_原创新药研究全国重点实验室
通讯作者Xu, Huae; Cai, Ying; Li, Yaping
作者单位1.Shanghai Jiao Tong Univ, Shanghai Gen Hosp, Precis Res Ctr Refractory Dis, Sch Med, Shanghai 201620, Peoples R China
2.Nanjing Med Univ, Sch Pharm, Natl Vaccine Innovat Platform, Nanjing 211166, Peoples R China
3.Chinese Acad Sci, Shanghai Inst Mat Med, Ctr Pharmaceut, Shanghai 201203, Peoples R China
4.Nanjing Med Univ, Sch Pharm, Dept Pharmaceut, Nanjing 211116, Peoples R China
5.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
6.Yantai Inst Pharmaceut Sci, Yantai Key Lab Nanomed & Adv Preparat, Yantai 264000, Shandong, Peoples R China
7.Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, Peoples R China
推荐引用方式
GB/T 7714		 Yan, Dan,Yi, Wenzhe,Wu, Ting,et al. Dual-sensitization nanoformulation combining glutamine metabolism inhibition and Fas/FasL activation for enhanced colorectal cancer immunotherapy[J]. JOURNAL OF CONTROLLED RELEASE,2025,388:14.
APA Yan, Dan.,Yi, Wenzhe.,Wu, Ting.,Hu, Shuangshuang.,Ding, Yan.,...&Li, Yaping.(2025).Dual-sensitization nanoformulation combining glutamine metabolism inhibition and Fas/FasL activation for enhanced colorectal cancer immunotherapy.JOURNAL OF CONTROLLED RELEASE,388,14.
MLA Yan, Dan,et al."Dual-sensitization nanoformulation combining glutamine metabolism inhibition and Fas/FasL activation for enhanced colorectal cancer immunotherapy".JOURNAL OF CONTROLLED RELEASE 388(2025):14.

入库方式： OAI收割

来源：上海药物研究所

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