Genetic engineering of systemically injectable oncolytic viruses for pyroptosis-accelerated cancer virotherapy

Area of Science:

• Oncology
• Virology
• Immunotherapy
• Biotechnology

Background:

• Systemic delivery of oncolytic viruses (OVs) faces challenges including neutralizing antibodies and low intratumoral bioavailability.
• Effective OV delivery requires strategies to overcome immune surveillance and ensure efficient tumor cell infection.

Purpose of the Study:

• To develop a novel, systemically injectable oncolytic virus delivery platform (iNV-GOV) for enhanced cancer therapy.
• To cloak OVs within immune-compatible cell membranes to evade immune detection and target tumors.
• To enable ultrasound-triggered, tumor-specific pyroptosis for accelerated oncolysis and viral amplification.

Main Methods:

• Genetically engineered cell membranes expressing chimeric antigen receptors were used to cloak OVs, forming the iNV-GOV platform.
• The OV payload included a heat-shock-inducible N-terminal gasdermin for ultrasound-activated pyroptosis.
• The platform's efficacy was evaluated in patient-derived xenograft models in humanized mice following systemic administration.

Main Results:

• The iNV-GOV platform successfully shielded OVs from immune recognition and efficiently targeted tumors.
• Ultrasound-induced mild hyperthermia triggered tumor-specific pyroptosis, leading to accelerated oncolysis.
• The treatment promoted rapid viral release, amplified infection of neighboring tumor cells, and elicited robust antitumor immunity.

Conclusions:

• The iNV-GOV platform represents a promising strategy for systemic delivery of OVs, overcoming key limitations.
• This tumor-targeted viral delivery system enables rapid and continuous intratumoral viral propagation.
• The developed platform holds potential for treating a wide range of cancers through enhanced oncolysis and immunotherapy.