As global cancer incidence approaches 30 million new annual cases by mid-century, conventional oncology's persistent failure points — systemic toxicity, non-specificity, and the resilience of cancer stem cells — demand entirely new therapeutic frameworks. Oncolytic virotherapy, now backed by over 250 active clinical trials worldwide, represents one of the most mechanistically distinct approaches to emerge in decades, and this comprehensive review consolidates where the field actually stands.
The mechanistic case for oncolytic viruses (OVs) rests on a dual-action model. First, these agents — either naturally tumor-tropic or genetically re-engineered for selectivity — infect and replicate exclusively within malignant cells, triggering direct lytic destruction. Second, and arguably more consequential, this lysis is immunogenic: the release of tumor-associated antigens and danger signals actively remodels the immunosuppressive tumor microenvironment, converting immunologically 'cold' tumors into 'hot' ones capable of recruiting cytotoxic T-cells against both primary lesions and distal metastases. The review maps this across four leading viral platforms — Adenovirus, Vaccinia virus, Herpes Simplex Virus-1 (HSV-1), and Reovirus — with particular clinical focus on melanoma, glioblastoma, and solid tumor indications.
This review arrives at a meaningful inflection point. The 2015 FDA approval of talimogene laherparepvec (T-VEC), an engineered HSV-1 derivative, remains the only approved OV in Western markets, underscoring how difficult clinical translation has been despite compelling preclinical data. The field's central unresolved tension — viral immune evasion versus anti-tumor immune activation — is precisely what newer engineering strategies attempt to navigate, using arming payloads, immune checkpoint co-delivery, and combination regimens with CAR-T or PD-1 inhibitors. As a review article rather than a primary trial, the work synthesizes existing evidence rather than generating new data, making its conclusions inherently limited by the quality and heterogeneity of the underlying studies. Nevertheless, for clinicians and researchers tracking immuno-oncology's frontier, this consolidation of mechanism, platform diversity, and trial landscape offers genuine orienting value in a rapidly evolving space.