Advancing clinical translation of oncolytic adenoviruses

Viruses are extraordinary products of evolution that can be harnessed as versatile platforms for cancer therapy. They replicate in tumor cells, induce lysis, and stimulate antitumor immunity. Among viral platforms, oncolytic adenoviruses (OAds) have emerged as leading candidates. They are well-characterized, amenable to genetic modification, capable of accommodating large payloads, and can be produced at high titers. Nonetheless, natural adenoviruses require precise engineering to maximize therapeutic benefit. Clinical translation has also been constrained by several barriers, including the absence of murine models permissive for adenovirus replication, immune neutralization during systemic delivery, and insufficient tumor penetration. This chapter explores strategies to overcome these challenges, beginning with an overview of the adenovirus replication cycle and its interaction with host cells and systemic factors. We discuss the intrinsic properties of the adenoviral life cycle that make these vectors effective oncolytic agents, as well as genetic modifications designed to further enhance antitumor efficacy. These include receptor retargeting, replication control, insertion of therapeutic payloads, and capsid protein engineering to ablate unwanted interactions with host factors. We also highlight clinically advanced OAds to illustrate which modifications have successfully moved beyond laboratory development into clinical application. In addition, the potential of alternative adenovirus types with distinct seroprevalence, replication machinery, and blood interactions is reviewed. Finally, we discuss advances in preclinical modeling, emphasizing the limitations of murine models and highlighting the development of immunocompetent hamster and porcine models that better reproduce adenovirus-host interactions and provide critical insights for clinical translation of OAds.