Circadian-guided oncolytic virotherapy for glioblastoma

Glioblastoma (GBM) remains one of the most aggressive and lethal malignancies, with clinical outcomes under the standard-of-care Stupp protocol remaining suboptimal. While oncolytic virus (OV) therapy has emerged as a mechanistically distinct and promising approach, its clinical success is frequently hindered by profound intratumoral heterogeneity and emerging resistance. This critical review proposes that the efficacy of virotherapy may be meaningfully enhanced by integrating circadian biology into treatment schedules; a paradigm termed "Oncolytic Chronovirotherapy." Recent evidence demonstrates that the infection cycle of neurotropic viruses, which serve as the scaffold for many OVs, is not a static process but is inherently regulated by the host's circadian clock. Fundamental studies reveal that the expression of essential viral entry receptors, such as Nectin-1 (for HSV-1) and p75NTR, exhibits robust circadian oscillations directly coordinated by the core molecular clock, specifically the BMAL1/CLOCK complex. Furthermore, the tumor immune microenvironment and cellular vulnerability to adjuvant chemotherapy (temozolomide) show synchronized peaks of activity, typically concentrated during the morning window, which often coincides with the nadir of DNA repair enzymes like MGMT. We argue that synchronizing OV administration with these windows of maximal receptor density and robust immune surveillance may maximize tumor lysis and facilitate the conversion of "cold" tumors into "hot," immune-responsive environments. The utilization of personalized circadian biomarkers and mathematical modeling to guide therapy delivery will be essential for the next generation of precision neuro-oncology.