Circadian-guided oncolytic virotherapy proposed to enhance glioblastoma lysis by synchronizing with host clock.

Glioblastoma (GBM) remains an exceptionally aggressive and lethal malignancy, with current standard-of-care, the Stupp protocol, yielding suboptimal outcomes. Oncolytic virus (OV) therapy offers a promising, mechanistically distinct approach, but its clinical success is often hampered by significant intratumoral heterogeneity and the development of resistance. This review addresses a critical gap by proposing that integrating circadian biology into OV treatment schedules could substantially enhance therapeutic efficacy, leveraging the inherent rhythmic nature of host-virus interactions and tumor biology.

This critical review synthesized existing evidence on the interplay between host circadian biology and neurotropic viral infection cycles, which serve as the scaffold for many oncolytic viruses (OVs). The authors analyzed fundamental studies demonstrating that the expression of essential viral entry receptors and the tumor immune microenvironment are under circadian regulation. They then proposed a novel paradigm, 'Oncolytic Chronovirotherapy,' advocating for the synchronization of OV administration with specific host circadian windows to maximize tumor lysis and immune activation, guided by personalized circadian biomarkers and mathematical modeling.

The review highlights that the infection cycle of neurotropic viruses, which are foundational for oncolytic viruses (OVs), is not static but inherently regulated by the host's circadian clock. Fundamental studies reveal that essential viral entry receptors, such as Nectin-1 (for HSV-1) and p75NTR, exhibit 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. The authors 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.