Tuning cellular metabolism for cancer virotherapy.

Oncolytic viruses (OVs) represent an emerging immunotherapeutic strategy owing to their capacity for direct tumor lysis and induction of antitumor immunity. However, hurdles like transient persistence and moderate efficacy necessitate innovative approaches. Metabolic remodeling has recently gained prominence as a strategic intervention, wherein OVs or combination regimens could reprogram tumor and immune cell metabolism to enhance viral replication and oncolysis. In this review, we summarize recent advances in strategic reprogramming of tumor and immune cell metabolism to enhance OV-based immunotherapies. Specific tactics include engineering viruses to target glycolytic, glutaminolytic, and nucleotide synthesis pathways in cancer cells, boosting viral replication and tumor cell death. Additionally, rewiring T cell and NK cell metabolism of lipids, amino acids, and carbohydrates shows promise to enhance antitumor effects. Further insights are discussed to pave the way for the clinical implementation of metabolically enhanced oncolytic platforms, including balancing metabolic modulation to limit antiviral responses while promoting viral persistence and tumor clearance. Key highlights of this paper are: • Elucidates the complex interplay between viral replication, cytolytic dynamics, and resultant immune activation profiles in the context of the immunosuppressed, metabolically stressed tumor microenvironment. • Underscores emerging tactics to reprogram tumor metabolism through viral engineering or metabolic modulation, enhancing glycolytic flux, glutaminolysis, redox balance, and nucleotide synthesis to heighten intratumoral viral activity. • Highlights novel perspectives on rewiring T cell and NK cell lipid, amino acid, and carbohydrate metabolism to augment functionality against malignancy and coordinate with oncolytic platforms. • Emphasizes throughout the delicate balance between productive oncolytic replication and immune-mediated viral clearance, providing insights into the rational design of metabolically augmented virotherapy. [ABSTRACT FROM AUTHOR]