Oncolytic HSV: Underpinnings of Tumor Susceptibility

Oncolytic herpes simplex virus (oHSV) is a therapeutic modality that has seen substantial success for the treatment of cancer, though much remains to be improved. Commonly attenuated through the deletion or alteration of the γ(1)34.5 neurovirulence gene, the basis for the success of oHSV relies in part on the malignant silencing of cellular pathways critical for limiting these viruses in healthy host tissue. However, only recently have the molecular mechanisms underlying the success of these treatments begun to emerge. Further clarification of these mechanisms can strengthen rational design approaches to develop the next generation of oHSV. Herein, we review our current understanding of the molecular basis for tumor susceptibility to γ(1)34.5-attenuated oHSV, with particular focus on the malignant suppression of nucleic acid sensing, along with strategies meant to improve the clinical efficacy of these therapeutic viruses.