Oncolytic reovirus: tumor-microenvironment remodeling, engineering constraints, and translational strategies.

Oncolytic reovirus (ReoV) has emerged as a promising cancer immunotherapy platform because of its natural tumor tropism and immunostimulatory properties. Reovirus enters susceptible cells through receptors including junctional adhesion molecule-A and exploits oncogenic signaling and impaired antiviral responses to preferentially replicate in tumor cells. Viral replication induces apoptosis and other context-dependent forms of programmed cell death, while tumor lysis promotes antigen release and immune activation. However, reovirus monotherapy has shown limited clinical efficacy because of circulating neutralizing antibodies, heterogeneous receptor expression, stromal barriers, and the immunosuppressive tumor microenvironment. Current strategies therefore combine reovirus with chemotherapy, radiotherapy, immune checkpoint blockade, and targeted agents, although treatment outcomes remain dependent on tumor type, dose, and scheduling. Unlike previous reviews focused primarily on reovirus biology or individual combination regimens, this review examines how reovirus remodels the tumor microenvironment and critically assesses the translational limitations of combination therapy. We further discuss reverse-genetics platforms, capsid and receptor-targeting modifications, immunomodulatory transgenes, and carrier-based delivery systems. Future development will require biomarker-guided patient selection, genetically stable viral constructs, optimized systemic delivery, and prospective evidence that immune activation produces clinically meaningful benefit.