IL-18-armed oncolytic vaccinia virus remodels the suppressive microenvironment via macrophage and Treg modulation in lymphoma

INTRODUCTION: Lymphoma is a heterogeneous hematological malignancy with limited effective therapies. Oncolytic vaccinia virus (OVV) is a promising immunotherapy, but its monotherapeutic efficacy is suboptimal, showing weak antitumor activity in murine lymphoma models and inducing an immunosuppressive tumor microenvironment (TME) with more M2 macrophages and Tregs. This study aimed to improve OVV's efficacy and translational feasibility by reversing the immunosuppressive TME and enhancing OVV-mediated antitumor immunity. METHODS: We first explored IL-18's effect on OVV-induced immunosuppressive TME, then engineered a recombinant OVV-hIL18 encoding human IL-18. We assessed its in vitro oncolytic activity, in vivo antitumor effect and safety in murine/humanized lymphoma models, and its TME-regulating mechanisms. RESULTS: IL-18 reversed OVV-induced immunosuppression by promoting M1 polarization and reducing Tregs, boosting OVV-mediated immunity. OVV-hIL18 had enhanced in vitro oncolysis, significantly inhibited tumor growth, prolonged survival in animal models without overt toxicity, and increased CD4⁺/CD8⁺ T cell infiltration, effector cytokine production and relieved T cell exhaustion in TME. CONCLUSION: IL-18-armed OVV overcomes OVV monotherapy limitations and enhances antitumor efficacy, providing theoretical and experimental support for its development as a next-generation immunotherapy for lymphoma.