Vaccinia virus for lung cancer therapy: preclinical progress and prospects as a systemic immunotherapy platform

Lung cancer remains a major therapeutic challenge, particularly when tumors resist targeted therapy or checkpoint blockade. Vaccinia virus (VV), historically used as a vaccine vector, is now being repurposed to selectively kill tumor cells while activating antitumor immunity. Beyond direct oncolysis, VV induces inflammatory cell death that recruits dendritic cells and reshapes tumor-immune interactions-a critical advantage in the immune-suppressed lung tumor microenvironment. This review highlights evidence from lung cancer models, detailing how specific VV strains modulate immunity and under which conditions these effects are therapeutically relevant. We discuss engineering strategies, from cytokine expression to enhanced costimulation, designed to convert "cold" tumors into responsive ones and enable rational combinations with checkpoint inhibitors. Early clinical data in non-small cell lung cancer are promising but also reveal key obstacles: inefficient systemic delivery and rapid immunosuppressive feedback within the tumor. Addressing these challenges will be essential for establishing VV as a robust systemic immunotherapy platform.