4.8 Article

Raddeanin A Enhances Mitochondrial DNA-cGAS/STING Axis-Mediated Antitumor Immunity by Targeting Transactive Responsive DNA-Binding Protein 43

Journal

ADVANCED SCIENCE
Volume 10, Issue 13, Pages -

Publisher

WILEY
DOI: 10.1002/advs.202206737

Keywords

dendritic cells; immune checkpoint therapies; immunogenic cell death; STING; transactive responsive DNA-binding protein 43

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The study identifies Raddeanin A (RA) as a potent immunogenic cell death (ICD) inducer that enhances antitumor immunity by inducing tumor cell immunogenicity and reprogramming the tumor microenvironment. RA directly binds to TDP-43 and induces its localization to mitochondria and mtDNA leakage, leading to upregulation of nuclear factor kappa B and type I interferon signaling and enhancing antigen cross-presentation and T cell activation.
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 kappa B 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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