<p>Oncolytic virotherapy (OVT) is a promising next-generation cancer treatment that utilizes oncolytic viruses that replicate preferentially in cancer cells but not in normal cells to selectively target and destroy cancer cells. Oncolytic viral vectors (OVVs) encompass both naturally occurring and genetically engineered viruses. Their efficacy relies on their capacity to target cancer cells via specific receptors, selectively replicate within malignant cells (rather than normal ones), and exploit abnormal signaling pathways that influence viral defense mechanisms. Clinical trials have demonstrated the safety and efficacy of various OVVs as standalone or combination treatments, with adenoviruses (AdVs), and herpes simplex viruses being the most commonly used. Moreover, RNA viruses such as alphaviruses (M1, Semliki Forest virus) and Orthoavulaviruses (Newcastle disease viruses) are frequently used as oncolytic viruses. Challenges include improving systemic administration, reducing costs, and addressing physical barriers and host immune responses. Future research should focus on investigating OVV-host immune system interactions within the tumor microenvironment and developing strategies to control transgene expression and administration timing to maximize the potential of multi-armed OVVs in cancer treatment. Combining OVVs with other immunotherapies and equipping them with immunomodulatory transgenes may yield significant results, but further optimization of delivery methods and overcoming barriers is necessary to fully realize the therapeutic potential of this approach.</p> Graphical Abstract <p></p>