Next-generation oncolytic virotherapy for lung cancer: bridging innovative vector engineering with clinical immunotherapy.

Lung cancer remains the leading cause of cancer‑related mortality worldwide, with resistance to immune checkpoint inhibitors (ICIs) posing a persistent therapeutic bottleneck for advanced‑stage patients, largely driven by an immunologically "cold" tumor microenvironment (TME). Oncolytic virotherapy has emerged as a paradigm‑shifting strategy to reverse this immunosuppressive phenotype through selective tumor lysis and robust systemic immune ignition. The aim of this review is to offer a comprehensive translational roadmap for oncolytic viruses (OVs) in lung cancer. We systematically dissect the molecular underpinnings of OV‑triggered immunogenic cell death-encompassing apoptosis, necroptosis, and autophagy-as well as their distinct and overlapping contributions to antitumor immunity. Critically, we evaluate major physiological barriers that impede effective systemic OV delivery, including hepatic sequestration, pre‑existing neutralizing antibodies, and tumor stromal obstruction, and showcase cutting‑edge bioengineering countermeasures, such as cell‑mediated carriers, including mesenchymal stem cells and peripheral blood mononuclear cells, extracellular matrix (ECM)‑degrading enzymes, and viruses armed with bispecific T‑cell engagers (BiTEs). We further synthesize the current clinical evidence, providing an updated appraisal of safety profiles, objective response rates, and biomarker‑driven outcomes from clinical trials. By bridging vector engineering innovations with real‑world clinical translation, this review establishes a strategic framework for advancing precision oncolytic immunotherapy in refractory lung cancer.