Selective Activation of Conditionally Replicating Influenza A Virus in Pulmonary Tumors for Enhanced Oncolytic Efficacy and Systemic Safety

Influenza A virus demonstrates significant potential as an oncolytic agent. Nevertheless, being replication‐competent pathogens, they may induce adverse effects in cancer patients who have compromised immune systems. Here, the results show that the 4‐hydroxytamoxifen (4‐HT)‐dependent H1N1 influenza virus S218 can inhibit the proliferation and lung metastasis of melanoma in vivo, and 4‐HT enhances the anti‐tumor effect of S218 virus. To activate the S218 virus in the tumors, tumor‐targeted nanostructured lipid carriers (NLCs) modified with folate (FA) are developed to encapsulate 4‐HT. This approach improves the tumor‐targeting capability and anti‐tumor immunity of the S218 virus. Furthermore, the combination of the S218 virus with the small molecule STING agonist SR717 further enhances the regression of lung metastases. The findings demonstrate a novel oncolytic strategy utilizing nanocarriers to deliver small‐molecule drugs for activating viruses in the tumors, offering insights for oncolytic virus development.