In vivo neutrophils hitchhiking for tumor targeting and microenvironment regulation boosts oncolytic virus therapy

Neutrophils constitute a substantial proportion of the immune cell population infiltrating tumors, where they play a pivotal role in establishing an immunosuppressive microenvironment to facilitate tumor growth. Our clinical investigation has unveiled that, following oncolytic virus (OV) treatment, immunosuppressive neutrophils could lead to T cell exhaustion and compromised antitumor efficacy. In this study, we devise a dual-functional conjugation strategy that enables OVs to selectively bind with circulating neutrophils and initiate their death. Prior to dysfunction, neutrophils can harbor OVs and facilitate their infiltration into tumors, leading to a 5.38-fold increase in OV levels within tumors compared to direct intravenous injection. Additionally, infiltrated neutrophils undergo dying after 8 h, which promotes T cell priming, reduces T cell exhaustion, and remodels the tumor immune microenvironment. Our findings illuminate the determinants influencing the efficacy of OVs and propose targeted solutions, thereby offering insights for the clinical translation of these therapeutic agents.