Viruses as cancer therapeutics: mechanisms of oncolytic virotherapy and key clinical platforms

Abstract

Oncolytic viruses (OVs) are emerging immunotherapeutic agents that selectively infect and destroy cancer cells while simultaneously stimulating anti-tumor immunity. This review examines how oncolytic virotherapy works at a mechanistic level and provides an overview of the leading OV platforms in clinical development. Virus-mediated lysis of tumor cells not only debulks tumors directly but also generates an in situ cancer vaccine effect by releasing tumor antigens and danger signals that activate the immune system. We discuss the biological and immunologic rationale behind this dual action, including the induction of immunogenic cell death and the conversion of "cold" tumors into "hot" immunologically active ones. Key molecular features of major oncolytic viruses – such as herpes simplex virus type 1–based Talimogene laherparepvec (T-VEC), oncolytic adenoviruses, reovirus, coxsackievirus (CVA21), and vaccinia virus – are reviewed, highlighting how genetic engineering (e.g., insertion of immune stimulatory genes) enhances their therapeutic impact. Early clinical results, including the first FDA-approved OV (T-VEC) in melanoma, demonstrate the promise of virotherapy. Combination approaches with immune checkpoint inhibitors are also introduced as a strategy to amplify anti-tumor responses. In summary, oncolytic virotherapy represents a novel modality at the intersection of virology and immuno-oncology. This article provides a comprehensive overview of OV mechanisms and platforms, underscoring the rationale for their use and their potential to broaden the horizons of cancer immunotherapy.