Delivery Strategies for Oncolytic Viruses in Gastrointestinal Cancers: Progress, Mechanisms and Clinical Translations

ABSTRACT

Due to their complex anatomy, high heterogeneity, and immunosuppressive tumour microenvironment, gastrointestinal cancers severely restrict the effective delivery and function of oncolytic viruses (OVs). This review summarises current multidimensional strategies to improve OV delivery efficiency. First, genetic engineering with deletion of viral genes and insertion of therapeutic genes, markedly enhance viral targeting, safety, and therapeutic capacity. Second, combination therapies with radiotherapy, chemotherapy and immunotherapy can execute microenvironmental preconditioning and either concurrent or sequential administration to improve viral distribution inside tumours, increase local accumulation and enhance immune activation. In addition, modulation of the tumour immune microenvironment helps enhance viral replication and spread in ‘cold’ tumours, thereby inducing systemic antitumour responses. Finally, carrier‐mediated delivery using stem cells, extracellular vesicles, and viral envelope reconstitution provides innovative approaches to overcome systemic delivery barriers. Despite persisting challenges such as rapid clearance, physical barriers, and viral inactivation, the strategies discussed in this review demonstrate significant advances in delivery mechanisms, immune synergy, and targeted accumulation, providing a solid foundation and new directions for the clinical translation of OVs in gastrointestinal tumours.