Integrating oncolytic adenoviruses into combination cancer therapy: Mechanisms, advances and clinical outlook

Abstract Background Cancer represents a major global public health issue, and recent research has focused on improving the efficacy of existing therapeutic approaches. In this context, oncolytic viruses have emerged as promising treatment options for advanced and treatment‐resistant malignancies. Among them, adenoviruses are the most extensively studied due to their favourable safety profile, biological versatility and ease of genetic modification to enhance therapeutic performance. Main body Combination‐based strategies integrating virotherapy with chemotherapy, radiotherapy or immunotherapy have been widely investigated to further improve anti‐tumour efficacy. These approaches act through complementary and synergistic mechanisms, where chemotherapy can promote viral replication and increase tumour cell susceptibility through deoxyribonucleic acid (DNA) damage and transient immunomodulation, while radiotherapy enhances immunogenic tumour cell death by inducing sustained DNA damage. In parallel, immunotherapy—particularly immune checkpoint inhibition—can strengthen anti‐tumour immunity by reversing T‐cell exhaustion and increasing CD8 + T‐cell infiltration and effector function. Collectively, these interactions amplify both direct viral oncolysis and immune‐mediated tumour clearance. Additionally, clinical trial data suggest that intravenous administration of oncolytic adenoviruses may provide greater systemic antit‐umour activity compared with intratumoural delivery, albeit with increased toxicity relative to localised injection. Conclusion Oncolytic adenoviruses have emerged as promising treatment options for advanced and treatment‐resistant malignancies, particularly when integrated with chemotherapy, radiotherapy or immunotherapy. However, most studies included are early‐phase trials conducted in small patient cohorts, underscoring the need for further research to better define safety profiles, long‐term adverse effects, and the underlying mechanisms driving therapeutic response.