Beyond HSV-1: Pseudorabies Virus as a Next-Generation Seronegative Backbone for Oncolytic Virotherapy

Oncolytic virotherapy has emerged as a promising strategy to combat cancer by exploiting viruses that selectively replicate in and destroy tumour cells. Among herpesviruses, herpes simplex virus type 1 (HSV-1) has served as the most extensively studied platform for the development of genetically engineered oncolytic viruses (OVs). However, its neurovirulence and widespread human seroprevalence pose safety concerns. Pseudorabies virus (PRV), a swine alphaherpesvirus not naturally pathogenic to humans, offers a compelling alternative. This review explores PRV’s biological features, mechanisms of cell entry, and genetic manipulability, highlighting its potential as a safe and versatile oncolytic platform. Advances in attenuation strategies, promoter targeting, and tropism modulation have enabled the development of recombinant PRVs with tumour-selective replication and reduced neurovirulence. Furthermore, PRV vectors armed with immunomodulatory transgenes have demonstrated potent antitumour efficacy and immune activation in preclinical models. Collectively, these findings position PRV as a promising candidate for next-generation oncolytic virotherapy, with potential to complement existing platforms.