Oncolytic virotherapy: Molecular mechanisms, delivery strategies, and translational insights

Area of Science:

• Oncology
• Immunology
• Virology

Background:

• Immunotherapy efficacy is limited by non-responsive tumors and suppressive tumor microenvironments (TME).
• Oncolytic virotherapy (OVT) offers a strategy to directly kill cancer cells and modulate the TME.
• OVT induces immunogenic cell death and type I interferon (IFN-I) signaling, enhancing anti-tumor immunity.

Purpose of the Study:

• To present clinical and preclinical evidence on OVT mechanisms, genetic engineering, and translational applications.
• To explore how OVT enhances immune priming and checkpoint inhibitor response.
• To bridge findings from companion animal oncology to human clinical trials.

Main Methods:

• Review of clinical trials and preclinical data involving oncolytic viruses.
• Analysis of genetic engineering strategies for OVT vector design and payloads.
• Examination of translational lessons across species, including companion animals.

Main Results:

• Clinical trials demonstrate OVT priming of checkpoint responses (e.g., DNX-2401 with pembrolizumab).
• Specific vector designs (e.g., TK-deleted vaccinia, CG0070) and payloads (e.g., IFNβ, NIS) show measurable clinical benefit.
• Evidence supports OVT's role in overcoming tumor resistance and enhancing immunotherapy.

Conclusions:

• Actionable priorities include patient selection based on IFN-pathway competence and receptor-tropism.
• Rational sequencing of OVT with immune checkpoint inhibitors (ICIs) is crucial.
• Further research and clinical translation are needed to accelerate durable responses in cancer patients.