Unlocking oncolytic virotherapy potential: leveraging bacteriophages to conquer immunosuppression

Oncolytic virotherapy (OVT) offers great potential as an immunotherapy by lysing cancer cells and inducing immunogenic cell death, inciting an anti-tumor immune response. However, immunosuppressive tumor microenvironments (TMEs) in "cold" solid tumors limit OVT effectiveness by reducing viral infiltration and immune responses. Bacteriophages-safe, manipulable bacterial viruses-and their derived mechanisms are emerging as promising tools to address this gap by minimizing TME immunosuppression, maximizing anti-tumor immune activation, and improving overall precision and effectiveness. Bacteriophage characteristics such as their repetitive peptide presentation, biological barrier degradation, and superior payload delivery capabilities can be harnessed for OVT to improve therapy effectiveness. This review explores how engineered OVT can leverage such bacteriophage-derived components through two main approaches. The established synergistic approach allows chimeric vectors such as AAVP to integrate phage safety, cargo capabilities, and precision into OVT. The proposed modular approach aims to transfer specific desirable traits from phages to replication-capable OVs. For example, through novel AI and genetic engineering technology, the first mammalian encoded hyaluronate lyase can be synthetically created. The products of this traditionally prokaryotic enzyme avoid the tumor-progressing effects of current mammalian extracellular matrix-degrading hyaluronate lyases.