Operation oncolysis: Reoviruses in the theater of cancer war

Reoviruses have emerged as promising oncolytic agents, exploiting their natural tropism for transformed cells with aberrant Ras signaling to enable selective replication and tumor cell lysis. The most clinically advanced candidate, Mammalian orthoreovirus Pelareorep (Reolysin), has demonstrated efficacy across multiple malignancies, including breast cancer, glioma, and pancreatic adenocarcinoma, with generally manageable safety profiles. Beyond Pelareorep, novel orthoreoviruses such as Avian orthoreovirus and Pteropine orthoreovirus have shown potent oncolytic activity and favorable tolerability in preclinical models, broadening the therapeutic landscape. Reovirus-based virotherapy exerts dual anti-tumor effects by inducing direct oncolysis and activating innate and adaptive immune responses, thereby enhancing outcomes when combined with chemotherapy or immune checkpoint inhibitors. Despite these advances, several barriers remain. Tumor heterogeneity and variable receptor expression affect viral infectivity and dissemination, while host immune responses, though critical for anti-tumor immunity, can also limit viral persistence and efficacy. Key mechanistic gaps persist in understanding reovirus-host interactions, particularly in immune modulation and cell death pathways. Furthermore, the optimal integration of reoviruses into combination regimens and clinical protocols requires further validation. Future efforts should emphasize biomarker-driven patient stratification, rational immunotherapeutic combinations to overcome tumor immunosuppression, and engineering of reovirus vectors to improve specificity and safety. Exploration of emerging orthoreoviruses with distinct biological properties also presents new opportunities for therapeutic innovation. Collectively, reoviruses represent a compelling platform at the forefront of precision oncolytic virotherapy, with translational potential hinging on the resolution of critical mechanistic and clinical challenges.