免疫原性细胞死亡
CD8型
T细胞
生物
癌症研究
免疫疗法
免疫系统
癌症免疫疗法
程序性细胞死亡
肿瘤微环境
细胞生物学
化学
免疫学
细胞凋亡
生物化学
作者
Mingxiao Yin,Jingwen Dong,Sun Cheng,Xiaojia Liu,Zhirui Liu,Lu Liu,Zean Kuang,Na Zhang,Dian Xiao,Xinbo Zhou,Hongbin Deng
标识
DOI:10.1002/advs.202206737
摘要
Immune checkpoint therapies (ICT) have achieved unprecedented efficacy in multiple cancer treatments, but are still limited by low clinical response rates. Identification of immunogenic cell death (ICD)-inducing drugs that can induce tumor cell immunogenicity and reprogram the tumor microenvironment is an attractive approach to enhance antitumor immunity. In the present study, Raddeanin A (RA), an oleanane class triterpenoid saponin isolated from Anemone raddeana Regel, is uncovered as a potent ICD inducer through an ICD reporter assay combined with a T cell activation assay. RA significantly increases high-mobility group box 1 release in tumor cells and promotes dendritic cell (DC) maturation and CD8+ T cell activation for tumor control. Mechanistically, RA directly binds to transactive responsive DNA-binding protein 43 (TDP-43) and induces TDP-43 localization to mitochondria and mtDNA leakage, leading to cyclic GMP-AMP synthase/stimulator of interferon gene-dependent upregulation of nuclear factor κB and type I interferon signaling, thereby potentiating the DC-mediated antigen cross-presentation and T cell activation. Moreover, combining RA with anti-programmed death 1 antibody effectively enhances the efficacy of ICT in animals. These findings highlight the importance of TDP-43 in ICD drug-induced antitumor immunity and reveal a potential chemo-immunotherapeutic role of RA in enhancing the efficacy of cancer immunotherapy.
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