*4.2. Metabolic Inhibitors as an Emerging Combination Therapy*

Given the OV dependence on host cell metabolism for replication, the metabolic pathways can be considered effective modalities in OVT. For example, due to the role of glycolysis in the antiviral response, blocking this pathway increases the sensitivity of cells to OV infection [273,274]. On the other hand, increasing pyruvate flux into the tricarboxylic acid cycle, the increment of oxidative phosphorylation, and reactive oxygen species production lead to enhance OV replication and oncolytic activity [275–277]. However, there are contradictions in the enhancing or dampening roles of these metabolic pathways in the replication and function of OVs [278]. These discrepancies indicate that the metabolic pathway targeting should be based on the type of cancer and employed OV. Tumor cells deplete the glucose, tryptophan, and glutamine required by immune cells and produce lactate, kynurenine, and adenosine [279]. These changes cause induction of exhausted CTLs, M2-macrophages, and Tregs, creating an immunosuppressive TME [275–278]. The

combination of metabolic inhibitors with OVT and the application of GMOVs to express metabolic inhibitors can alter the metabolism of cancer cells and immune cells to increase antitumor responses [278,280].
