Overcoming barriers in cancer therapy with oncolytic adenoviruses: Engineering strategies and clinical perspectives.

Oncolytic adenoviruses (OADVs) have emerged as promising therapeutics for cancer treatment, offering tumour-selective replication and potent antitumor effects. These genetically engineered viruses infect and lyse cancer cells while simultaneously activating antitumor immunity. OADV can be engineered with therapeutic genes and tumour-specific promoters, further enhancing their specificity and efficacy. Various researchers have explored the use of OADV in cancer treatment, integrating direct oncolysis with immune activation, hence revealing promising therapeutic effects in preclinical studies. This review provides comprehensive insights into the mechanism of OADV engineering with tumor-specific promoters and therapeutic payloads, emphasizing advances in vector design that enhance specificity and efficacy. Key evidence from preclinical and clinical studies across lungs, pancreatic, hepatic, breast, renal, and brain cancers is highlighted, demonstrating the translational impact of OADV therapy. The synergistic potential of OADVs in combination regimens, including chemotherapy, immunotherapy, and gene therapy, is critically appraised. The review further examines central hurdles such as antiviral immunity, tumor microenvironment complexity, and delivery challenges, discussing innovative strategies like genetic modulation and nanoparticle carriers to overcome these barriers. Through integrating direct oncolysis and immune modulation, OADVs offer a multifaceted approach for the treatment of resistant and heterogeneous malignancies. The future of OADV therapy requires continued refinement in vector engineering, personalized delivery systems, and multidisciplinary research, positioning OADVs as pivotal agents for enhancing patient outcomes and quality of life in cancer care.