ArticleJournal for immunotherapy of cancer2023
PKR induces TGF-β and limits oncolytic immune therapy.
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 16 papers.
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Who cites it
16 citing papers in PubMed, 14 citations in OpenAlex.
- Next-generation oncolytic virotherapy for lung cancer: bridging innovative vector engineering with clinical immunotherapy.Translational lung cancer research · 2026Review
- BTK inhibition enhances immunovirotherapy in glioblastoma via tertiary lymphoid structure modulation.bioRxiv : the preprint server for biology · 2026Article
- The integrated stress response in cancer: mechanisms of tumor adaptation and therapeutic targeting.Biochemical Society transactions · 2026Review
- Identification of ADAR1i-124: The first effective A-to-I RNA editing inhibitor with promising cancer therapeutic potential.iScience · 2026Article
- Crosstalk in the brain tumor microenvironment: mechanisms, therapeutic strategies, and clinical advances.Military Medical Research · 2026Review
- Immunological Biomarkers in Glioblastoma: Targeting T and NK Cells for Enhanced Diagnosis and Prognosis.Biologics : targets & therapy · 2026Review
- Enhanced oral nanomedicine utilizing biomineralized oncolytic virus for synergistic gastrointestinal cancer therapy.Materials today. Bio · 2025Article
- Oncolytic HSV and cancer drug interactions: Current clinical status and future directions.Molecular therapy : the journal of the American Society of Gene Therapy · 2025Review
- IDH status dictates oHSV mediated metabolic reprogramming affecting anti-tumor immunity.Nature communications · 2025Article
- β-blocker suppresses both tumoral sympathetic neurons and perivascular macrophages during oncolytic herpes virotherapy.Journal for immunotherapy of cancer · 2025Article
- Blocking Feedback Immunosuppression of Antigen Presentation in Brain Tumor During Oncolytic Virotherapy with oHSV-mshPKR.Molecular cancer therapeutics · 2025Article
- Immune Checkpoint Inhibitors Combined with Oncolytic Virotherapy: Synergy, Heterogeneity, and Safety in Cancer Treatment.Oncology research · 2025Review
- Article
- Glabridin improves autoimmune disease in Trex1-deficient mice by reducing type I interferon production.Molecular medicine (Cambridge, Mass.) · 2023Article
- Brain CD73 modulates interferon signaling to regulate glioblastoma invasion.Neuro-oncology advancesArticle
- Immunocompetent murine glioblastoma stem-like cell models exhibiting distinct phenotypes.Neuro-oncology advancesArticle
Corrections and comments
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Authors and funding
13 authors at 2 institutions in 1 country.
Funding
Abstract
backgroundMammalian cells have developed multiple intracellular mechanisms to defend against viral infections. These include RNA-activated protein kinase (PKR), cyclic GMP-AMP synthase and stimulation of interferon genes (cGAS-STING) and toll-like receptor-myeloid differentiation primary response 88 (TLR-MyD88). Among these, we identified that PKR presents the most formidable barrier to oncolytic herpes simplex virus (oHSV) replication in vitro.
methodsTo elucidate the impact of PKR on host responses to oncolytic therapy, we generated a novel oncolytic virus (oHSV-shPKR) which disables tumor intrinsic PKR signaling in infected tumor cells.
resultsAs anticipated, oHSV-shPKR resulted in suppression of innate antiviral immunity and improves virus spread and tumor cell lysis both in vitro and in vivo. Single cell RNA sequencing combined with cell-cell communication analysis uncovered a strong correlation between PKR activation and transforming growth factor beta (TGF-ß) immune suppressive signaling in both human and preclinical models. Using a murine PKR targeting oHSV, we found that in immune-competent mice this virus could rewire the tumor immune microenvironment to increase the activation of antigen presentation and enhance tumor antigen-specific CD8 T cell expansion and activity. Further, a single intratumoral injection of oHSV-shPKR significantly improved the survival of mice bearing orthotopic glioblastoma. To our knowledge, this is the first report to identify dual and opposing roles of PKR wherein PKR activates antivirus innate immunity and induces TGF-ß signaling to inhibit antitumor adaptive immune responses.
conclusionsThus, PKR represents the Achilles heel of oHSV therapy, restricting both viral replication and antitumor immunity, and an oncolytic virus that can target this pathway significantly improves response to virotherapy.
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