Immunological Impact of Oncolytic Adenoviruses On Cancer Therapy: Clinical Insights

Oncolytic immunotherapy, particularly using engineered adenoviruses, has emerged as a promising approach in cancer treatment due to its dual mechanism of action: selective tumor-cell destruction and inducing potent antitumor immune responses. This review focuses on the immunological effects observed in clinical trials involving conditionally replicating oncolytic adenoviruses (OAds), either with or without transgenes. These viruses primarily exert antitumor effects through mechanisms like direct oncolysis, apoptosis, necroptosis, and autophagy, while also activating innate and adaptive immune responses. Different genetic modification strategies have been employed to enhance the safety and therapeutic efficacy of OAds. However, these alterations may influence viral replication dynamics, oncolytic potency, and the duration of viral presence (i.e., persistence) within the tumor. Clinical data have shown that OAds can also profoundly alter the tumor microenvironment (TME), converting cold tumors to hot by increasing immune cell infiltration and activation. This conversion not only correlates with improved clinical outcomes but also creates conditions conducive to the efficacy of other immunotherapies, particularly immune checkpoint inhibitors (ICIs), which traditionally show limited activity in cold tumors. The synergistic potential of combining OAds with ICIs has shown promising results in improving clinical response rates. However, maximizing therapeutic benefit requires careful consideration of the OAd's immune-activating capabilities and optimal timing of combination strategies. This review provides critical insights into the current state of OAd-based immunotherapy, examining its role in modulating the TME, while addressing the complex interplay between oncolytic activity and sustained immune stimulation in clinical practice.