Raddeanin A Enhances Mitochondrial DNA-cGAS/STING Axis-Mediated Antitumor Immunity by Targeting Transactive...

Area of Science:

• Oncology
• Immunology
• Pharmacology

Background:

• Immune checkpoint therapies (ICT) show promise in cancer treatment but have limited response rates.
• Identifying drugs that induce immunogenic cell death (ICD) is crucial for enhancing anti-tumor immunity.
• Reprogramming the tumor microenvironment can improve therapeutic outcomes.

Purpose of the Study:

• To investigate Raddeanin A (RA) as a potential inducer of immunogenic cell death (ICD).
• To elucidate the mechanism by which RA enhances anti-tumor immunity.
• To evaluate the synergistic effect of RA with ICT in cancer treatment.

Main Methods:

• ICD reporter assay and T cell activation assay were used to identify RA as an ICD inducer.
• Assessed RA's effect on high-mobility group box 1 (HMGB1) release and dendritic cell (DC) maturation.
• Investigated RA's mechanism involving transactive responsive DNA-binding protein 43 (TDP-43), mitochondrial localization, and downstream signaling pathways (cGAS-STING, NF-κB, type I IFN).
• Evaluated the combination therapy of RA with anti-programmed death 1 (PD-1) antibody in animal models.

Main Results:

• Raddeanin A (RA) was identified as a potent ICD inducer.
• RA promoted tumor cell HMGB1 release, DC maturation, and CD8+ T cell activation.
• RA directly binds to TDP-43, inducing its mitochondrial localization, mtDNA leakage, and subsequent activation of cGAS-STING, NF-κB, and type I interferon signaling pathways.
• Combination of RA with anti-PD-1 antibody significantly enhanced ICT efficacy in vivo.

Conclusions:

• Raddeanin A (RA) acts as an ICD inducer by modulating TDP-43 and related signaling pathways.
• RA potentiates DC-mediated antigen cross-presentation and T cell activation.
• RA demonstrates potential as a chemo-immunotherapeutic agent to enhance cancer immunotherapy efficacy, particularly in combination with ICT.