Hemin blocks TIGIT/PVR interaction and induces ferroptosis to elicit synergistic effects of cancer immunotherapy

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外文摘要：The immune checkpoint TIGIT/PVR blockade exhibits significant antitumor effects through activation of NK and CD8+T cell-mediated cytotoxicity.Immune checkpoint blockade(ICB)could induce tumor ferroptosis through IFN-γ released by immune cells,indicating the synergetic effects of ICB with ferroptosis in inhibiting tumor growth.However,the development of TIGIT/PVR inhibitors with ferroptosis-inducing effects has not been explored yet.In this study,the small molecule Hemin that could bind with TIGIT to block TIGIT/PVR interaction was screened by virtual molecular docking and cell-based blocking assay.Hemin could effectively restore the IL-2 secretion from Jurkat-hTIGIT cells.Hemin reinvigorated the function of CD8+T cells to secrete IFN-γ and the elevated IFN-γ could synergize with Hemin to induce ferroptosis in tumor cells.Hemin inhibited tumor growth by boosting CD8+T cell immune response and inducing ferroptosis in CT26 tumor model.More importantly,Hemin in combination with PD-1/PD-L1 blockade exhibited more effective antitumor efficacy in anti-PD-1 resistant B16 tumor model.In summary,our finding indicated that Hemin blocked TIGIT/PVR interaction and induced tumor cell fer-roptosis,which provided a new therapeutic strategy to combine immunotherapy and ferroptosis for cancer treatment.

外文关键词：

cancer immunotherapyTIGIT/PVRsmall moleculeHeminferroptosis

作者：

Xiaowen Zhou、Yang Li、Xiangrui Zhang、Beibei Li、Shengzhe Jin、Menghan Wu、Xiuman Zhou、Qingyu Dong、Jiangfeng Du、Wenjie Zhai、Yahong Wu、Lu Qiu、Guodong Li、Yuanming Qi、Wenshan Zhao、Yanfeng Gao

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作者单位：

School of Life Sciences,Zhengzhou University,Zhengzhou 450001,China

School of Pharmaceutical Sciences(Shenzhen),Shenzhen Campus of Sun Yat-sen University,Shenzhen 518107,China

基金：

National Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaHenan Provincial Science and Technology Research ProjectShenzhen Science and Technology Program"Pearl River Talent Plan"Innovation and Entrepreneurship Team Project of Guangdong ProvinceGuangdong Basic and Applied Basic Research FoundationFostering Project for Young Teachers of Zhengzhou University

项目编号：

U190414731700677U20A2036982272785232102311172KQTD201909291738533972019ZT08Y4642022B1515120085JC22851042

出版年：

2024

DOI：

10.1007/s11427-023-2472-4

中国科学:生命科学(英文版)

中国科学院

中国科学:生命科学(英文版)

CSTPCD

影响因子：0.806

ISSN：1674-7305

年,卷(期)：2024.67(5)