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

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 

机构地区：[1]School of Life Sciences,Zhengzhou University,Zhengzhou 450001,China [2]School of Pharmaceutical Sciences(Shenzhen),Shenzhen Campus of Sun Yat-sen University,Shenzhen 518107,China

出　　处：《Science China(Life Sciences)》2024年第5期996-1009,共14页中国科学（生命科学英文版）

基　　金：supported by the National Natural Science Foundation of China(U1904147,31700677,U20A20369,82272785);Henan Provincial Science and Technology Research Project(232102311172);Shenzhen Science and Technology Program(KQTD20190929173853397);“Pearl River Talent Plan”Innovation and Entrepreneurship Team Project of Guangdong Province(2019ZT08Y464);the Guangdong Basic and Applied Basic Research Foundation(2022B1515120085);Fostering Project for Young Teachers of Zhengzhou University(JC22851042)。

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-γreleased 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 withTIGIT 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-γand the elevated IFN-γcould 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 ferroptosis,which provided a new therapeutic strategy to combine immunotherapy and ferroptosis for cancer treatment.

关 键 词：cancer immunotherapy TIGIT/PVR small molecule HEMIN ferroptosis 

分 类 号：R730.51[医药卫生—肿瘤]