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Icariside I enhances the effects of immunotherapy in gastrointestinal cancer via targeting TRPV4 and upregulating the cGAS-STING-IFN-I pathway
- Source :
- Biomedicine & Pharmacotherapy, Vol 177, Iss , Pp 117134- (2024)
- Publication Year :
- 2024
- Publisher :
- Elsevier, 2024.
-
Abstract
- Gastrointestinal cancer is among the most common cancers worldwide. Immune checkpoint inhibitor-based cancer immunotherapy has become an innovative approach in cancer treatment; however, its efficacy in gastrointestinal cancer is limited by the absence of infiltration of immune cells within the tumor microenvironment. Therefore, it is therefore urgent to develop a novel therapeutic drug to enhance immunotherapy. In this study, we describe a previously unreported potentiating effect of Icariside I (ICA I, GH01), the main bioactive compound isolated from the Epimedium species, on anti-tumor immune responses. Mechanistically, molecular docking and SPR assay result show that ICA I binding with TRPV4. ICA I induced intracellular Ca2+ increasing and mitochondrial DNA release by targeting TRPV4, which triggered cytosolic ox-mitoDNA release. Importantly, these intracellular ox-mitoDNA fragments were taken up by immune cells in the tumor microenvironment, which amplified the immune response. Moreover, our study shows the remarkable efficacy of sequential administration of ICA I and anti-α-PD-1 mAb in advanced tumors and provides a strong scientific rationale for recommending such a combination therapy for clinical trials. ICA I enhanced the anti-tumor effects with PD-1 inhibitors by regulating the TRPV4/Ca2+/Ox-mitoDNA/cGAS/STING axis. We expect that these findings will be translated into clinical therapies, which will benefit more patients with cancer in the near future.
Details
- Language :
- English
- ISSN :
- 07533322
- Volume :
- 177
- Issue :
- 117134-
- Database :
- Directory of Open Access Journals
- Journal :
- Biomedicine & Pharmacotherapy
- Publication Type :
- Academic Journal
- Accession number :
- edsdoj.4b4152e3c88e46839f6ef41642d87109
- Document Type :
- article
- Full Text :
- https://doi.org/10.1016/j.biopha.2024.117134