ArticleJournal for immunotherapy of cancer2023
Caspase-9 inhibition triggers Hsp90-based chemotherapy-mediated tumor intrinsic innate sensing and enhances antitumor immunity.
Article in Journal for immunotherapy of cancer, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed, 22 citations in OpenAlex.
- Heat Shock Protein 90: From Molecular Chaperone Function to Therapeutic Targeting in Malignancies.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Review
- Profiles of FGF2, HGF, Fas/CD95, CASP9, ALDH1A1, and GLUT1 in GEP-NETs: A Comparative Tumor-Margin Study Based on Protein Concentration.International journal of molecular sciences · 2026Article
- Apolipoprotein D downregulation in OSCC: multi-database validation and clinical significance.BMC medical genomics · 2026Article
- Targeting HSP90 in cancer: advances in the development of inhibitors, mechanisms of action, and therapeutic applications.Molecular cancer · 2026Review
- PD1 cell membrane-coated Ru(ll)-Pt(lV) complex nanoparticles inhibit liver metastatic melanoma via cascade immune activation.Journal of nanobiotechnology · 2026Article
- Antiproliferative Effect of Okra Seed Protein Isolate against HepG2 and A549 Cell Lines.Chemistry & biodiversity · 2026Article
- Anti PD-L1 immunotherapy alters macrophage phenotypes via EGR1 and HSP90AB1 supported by integrated methodologies.Scientific reports · 2025Article
- Caspase-9 activates β-catenin signaling to promote pulmonary fibrosis.Journal of translational medicine · 2025Article
- Unlocking the therapeutic potential of the STING signaling pathway in anti-tumor treatment.Clinical and experimental medicine · 2025Review
- Hsp90Pharmaceuticals (Basel, Switzerland) · 2025Review
- CD19-targeted HSP90 inhibitor nanoparticle combined with TKIs reduces tumor burden and enhances T-cell immunity in murine B-cell malignancies.Theranostics · 2025Article
- A novel pyroptosis-related gene signature exhibits distinct immune cells infiltration landscape in Wilms' tumor.BMC pediatrics · 2024Article
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Authors and funding
10 authors at 1 institution in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundAntineoplastic chemotherapies are dramatically efficient when they provoke immunogenic cell death (ICD), thus inducing an antitumor immune response and even tumor elimination. However, activated caspases, the hallmark of most cancer chemotherapeutic agents, render apoptosis immunologically silent. Whether they are dispensable for chemotherapy-induced cell death and the apoptotic clearance of cells in vivo is still elusive.
methodsA rational cell-based anticancer drug library screening was performed to explore the immunogenic apoptosis pathway and therapeutic targets under apoptotic caspase inhibition. Based on this screening, the potential of caspase inhibition in enhancing chemotherapy-induced antitumor immunity and the mechanism of actions was investigated by various cells and mouse models.
resultsHeat shock protein 90 (Hsp90) inhibition activates caspases in tumor cells to produce abundant genomic and mitochondrial DNA fragments and results in cell apoptosis. Meanwhile, it hijacks Caspase-9 signaling to suppress intrinsic DNA sensing. Pharmacological blockade or genetic deletion of Caspase-9 causes tumor cells to secrete interferon (IFN)-β via tumor intrinsic mitochondrial DNA/the second messenger cyclic GMP-AMP (cGAS) /stimulator of interferon genes (STING) pathway without impairing Hsp90 inhibition-induced cell death. Importantly, both Caspase-9 and Hsp90 inhibition triggers an ICD, leading to the release of numerous damage-associated molecular patterns such as high-mobility group box protein 1, ATP and type I IFNs in vitro and remarkable antitumor effects in vivo. Moreover, the combination treatment also induces adaptive resistance by upregulating programmed death-ligand 1 (PD-L1). Additional PD-L1 blockade can further overcome this acquired immune resistance and achieve complete tumor regression.
conclusionsBlockade of Caspase-9 signaling selectively provokes Hsp90-based chemotherapy-mediated tumor innate sensing, leading to CD8
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