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.