Oncolytic herpes simplex virus 1 (oHSV) is a promising viro-immunotherapy that directly lyses tumor cells while reshaping the tumor microenvironment (TME) and stimulates anti-tumor immunity. However, despite encouraging preclinical and clinical activity, treatment-induced adaptations in tumor cells and the surrounding microenvironment can promote survival, repair, repopulation, immune escape, and recurrence, thereby limiting durable therapeutic benefit. In our recent article published in Cell Death & Disease,1 we asked why oHSV often fails to achieve durable tumor control and whether the adaptive resistance it induces can be therapeutically overcome.