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

Abstract

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.

Biomaterials Facilitating Dendritic Cell‐Mediated Cancer Immunotherapy

“…[ 253 ] Therefore, combination of chemotherapy and DC‐mediated immunotherapy may potentiate the therapeutic efficacy by killing tumor cells and augmentation of host immune system. [ 254 ] Fan et al first utilized mitoxantrone to induce ICD of tumor cells and release immunostimulatory ligands. Subsequently, they applied nano‐depot platform to load immunostimulatory ligands and conjugate them with immunogenically dying tumor cells.…”

Mitochondrial DNA-targeted therapy: A novel approach to combat cancer

“…And Yin et al. ( Yin et al, 2023 ) discovered the special effect of Raddeanin A in tumor immunotherapy, which is an oleanane class triterpenoid saponin isolated from Anemone raddeana Regel. It has the ability to interact with the transactive responsive DNA-binding protein 43 (TDP-43), trigger the release of mtDNA from mitochondria, and consequently enhance dendritic cells (DCs) mediated antigen cross-presentation and T cell activation.…”

“… Pancreatic cancer 2023 Yin et al. ( Yin et al, 2023 ) Activate immunity Raddeanin A It could bind to TDP-43, induce mtDNA leakage, and ultimately enhance DC-mediated antigen cross-presentation and T cell activation. Melanoma and colon cancer 2023 Xiao et al.…”

Gas-Amplified Metalloimmunotherapy with Dual Activation of Pyroptosis and the STING Pathway for Remodeling the Immunosuppressive Cervical Cancer Microenvironment

“…On the other hand, the cGAS-STING pathway is a crucial innate immune pathway that plays a crucial role in activating antitumor immunity . Activation of the cGAS-STING pathway can activate TIDCs, enabling them to effectively present tumor antigens and anti-inflammatory substances released during pyroptosis to T cells. , Therefore, simultaneous activation of the cGAS-STING pathway while inducing pyroptosis is expected to fully activate the immune pathway and amplify the adaptive immune response induced by pyroptosis. Among various cGAS-STING agonists, Mn 2+ has been shown to activate cGAS-STING signaling even in the absence of double-stranded DNA, thereby stimulating DC maturation .…”