Development of a New Oncolytic Virus Platform to Overcome Systemic Delivery Challenges

Oncolytic viruses (OVs) represent a promising frontier in cancer therapy. These replication-competent viruses can infect both normal and tumor cells but selectively replicate within the latter, triggering an anti-tumor response. While the first FDA-approved OV therapy, Imlygic (based on HSV), has succeeded in treating melanoma via intratumoral injection, its efficacy remains limited against deep-seated or metastatic tumors.

To address these challenges, systemic administration of OVs has become a primary research focus to improve clinical outcomes for hard-to-reach cancers. However, previous studies have highlighted several hurdles, including rapid clearance by pre-existing neutralizing antibodies and potential systemic toxicity. Increasing the dose to improve delivery efficiency often escalates the risk of severe side effects or even patient mortality. Consequently, there is an urgent need for a balanced approach that enhances delivery to the tumor while reducing the required dosage.

Recently, researchers published a study in the journal Nature Cancer titled "Genetic engineering of systemically injectable oncolytic viruses for pyroptosis-accelerated cancer virotherapy." The study introduces iNV-GOV, a systemically injectable and tumor-targeted delivery platform. This platform protects viral particles from immune recognition while guiding them to tumor sites, accelerating cancer cell pyroptosis and eliciting a robust anti-tumor immune response.

The systemic delivery of OVs is typically hindered by neutralizing antibodies and low intratumoral bioavailability. In this study, the team developed immune-compatible cell membranes engineered to express chimeric antigen receptors (CARs) to encapsulate the viruses. This membrane structure acts as a "stealth cloak" to evade the immune system, while the CAR structure serves as a "navigation system" to target tumors.

The OV payload encodes N-terminal gasdermin under the control of a heat shock promoter. This allows ultrasound-induced mild hyperthermia to trigger tumor-specific pyroptosis, which accelerates tumor lysis and facilitates the rapid release of OVs from lysed cells. This process enhances the infection of neighboring tumor cell populations.

Figure 1. GOV^US treatment enhances OV replication and cytotoxic activity. (Chen X, et al., 2026)

Following systemic administration, iNV-GOV efficiently targets and infects tumor cells, induces pyroptosis upon ultrasound activation, and triggers a strong anti-tumor immune response in patient-derived xenograft models using humanized mice. The entire process initiates a self-enhancing chain reaction, forming a continuous cycle of pyroptosis, lysis, infection, and killing, thereby amplifying the therapeutic effect.

This technology integrates cancer virotherapy, cell membrane coating, CAR targeting, and controlled pyroptosis into a powerful positive feedback loop. It not only overcomes the issues of low delivery efficiency and poor safety but also significantly enhances anti-tumor immunity, offering a highly promising strategy for treating metastatic cancer.

Reference

Chen X, et al. Genetic engineering of systemically injectable oncolytic viruses for pyroptosis-accelerated cancer virotherapy. Nature Cancer, 2026: 1-17.