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Updated: Jun 27, 2025
Paramyxoviruses for Tumor-targeted Immunomodulation: Design and Evaluation Ex Vivo
Published on: January 7, 2019
Fn-OMV potentiates ZBP1-mediated PANoptosis triggered by oncolytic HSV-1 to fuel antitumor immunity
Shuo Wang1, An Song1, Jun Xie1,2
1State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Frontier Science Center for Immunology and Metabolism, Taikang Center for Life and Medical Sciences, Wuhan University, Wuhan, 430079, China.
Abstract:
Oncolytic viruses (OVs) show promise as a cancer treatment by selectively replicating in tumor cells and promoting antitumor immunity. However, the current immunogenicity induced by OVs for tumor treatment is relatively weak, necessitating a thorough investigation of the mechanisms underlying its induction of antitumor immunity. Here, we show that HSV-1-based OVs (oHSVs) trigger ZBP1-mediated PANoptosis (a unique innate immune inflammatory cell death modality), resulting in augmented antitumor immune effects. Mechanistically, oHSV enhances the expression of interferon-stimulated genes, leading to the accumulation of endogenous Z-RNA and subsequent activation of ZBP1. To further enhance the antitumor potential of oHSV, we conduct a screening and identify Fusobacterium nucleatum outer membrane vesicle (Fn-OMV) that can increase the expression of PANoptosis execution proteins. The combination of Fn-OMV and oHSV demonstrates potent antitumor immunogenicity. Taken together, our study provides a deeper understanding of oHSV-induced antitumor immunity, and demonstrates a promising strategy that combines oHSV with Fn-OMV.
Insights
Oncolytic viruses (oHSVs) trigger ZBP1-mediated PANoptosis, enhancing antitumor immunity. Combining oHSVs with Fusobacterium nucleatum outer membrane vesicles (Fn-OMV) further boosts this potent cancer treatment strategy.
Area of Science:
- Immunology
- Virology
- Oncology
Background:
- Oncolytic viruses (OVs) are promising cancer therapeutics due to their tumor-selective replication and ability to stimulate anti-tumor immunity.
- The immunogenicity of current OVs for cancer treatment remains limited, requiring deeper understanding of immune induction mechanisms.
Purpose of the Study:
- To elucidate the mechanisms of HSV-1-based oHSV-induced antitumor immunity.
- To identify strategies for enhancing the immunotherapeutic potential of oHSVs.
Main Methods:
- Investigated HSV-1-based oHSVs' interaction with innate immune pathways.
- Utilized screening to identify synergistic agents for oHSV therapy.
- Assessed combined efficacy of oHSV and identified agents in preclinical models.
Main Results:
- HSV-1-based oHSVs induce ZBP1-mediated PANoptosis, a novel inflammatory cell death pathway.
- oHSVs enhance interferon-stimulated gene expression, leading to Z-RNA accumulation and ZBP1 activation.
- Fusobacterium nucleatum outer membrane vesicles (Fn-OMV) were identified to enhance PANoptosis execution proteins, significantly boosting oHSV's anti-tumor immune effects.
Conclusions:
- oHSVs activate ZBP1-mediated PANoptosis, augmenting anti-tumor immunity.
- Combination therapy with Fn-OMV and oHSV presents a potent strategy for enhanced cancer immunotherapy.
- This study deepens the understanding of oHSV-mediated immune responses and offers a novel therapeutic approach.
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