Abstract

Oncolytic viruses (OVs) represent a novel and promising approach in cancer treatment, leveraging their ability to selectively infect, replicate within, and destroy tumor cells while sparing normal tissues. Recent advances in epigenetics have highlighted the potential of OVs to modulate the tumor epigenome, thus enhancing their therapeutic efficacy. This review explores the intersection of oncolytic virus therapy and epigenetic reprogramming, focusing on how OVs can alter key epigenetic mechanisms, such as DNA methylation, histone modification, and non-coding RNA expression, to disrupt tumor progression and immune evasion. We discuss the ability of OVs to reverse cancer-associated epigenetic changes, reactivating silenced tumor suppressor genes and sensitizing tumors to immune checkpoint inhibitors and other therapies. Furthermore, engineered OVs capable of delivering epigenetic modulators directly to tumor cells offer a dual mechanism of action, combining direct oncolysis with targeted epigenetic reprogramming. Preclinical and clinical evidence supporting the synergy between OVs and epigenetic therapy is reviewed, highlighting key challenges, including delivery optimization, resistance mechanisms, and immune response modulation. This article underscores the transformative potential of integrating OVs with epigenetic therapies, paving the way for innovative cancer treatment strategies. As the field progresses, understanding the molecular interplay between oncolytic virotherapy and the epigenome will be crucial for developing next-generation therapeutic platforms.