Scientists have reported a significant advance in the fight against glioblastoma (GBM), an aggressive brain cancer that remains largely resistant to modern immunotherapy. The team has created a highly modified version of herpes simplex virus type 1 that can directly attack tumour cells while sparking a powerful immune response inside the brain. The results in preclinical models suggest a promising new approach for a disease that currently leaves most patients with a short life expectancy and limited treatment options.
Precision targeting while protecting healthy brain cells
The engineered therapy is based on the MacIntyre strain of herpes virus, chosen for its strong ability to kill cancer cells. Researchers introduced a series of mutations to improve its spread through GBM tumours and to reduce the risk of the virus changing over time. Importantly, they altered its behaviour so it cannot infect neurons, helping to ensure the surrounding healthy brain tissue remains unharmed.
To strengthen safety further, the team inserted special microRNA target sequences that prevent the virus from replicating in normal brain cells. They also redesigned the viral envelope protein known as gD, enabling it to recognise molecular features that are abundant on GBM cells, including EGFR and certain integrins. This targeting system ensures the virus attaches to and invades cancer cells with far greater precision than earlier versions. The therapy can also be tracked using PET imaging, meaning doctors would be able to monitor how it spreads inside the tumour.
Immune system activation from inside the tumour
Glioblastoma is known to create a highly suppressive tumour microenvironment that blocks the body’s normal defences. To counteract this, the virus was equipped with five additional molecules that stimulate immune activity once it reaches the tumour. These include IL 12, a potent immune activator, an anti PD1 antibody that lifts a common brake on immune cells, a bispecific T cell engager to strengthen cancer cell recognition, an enzyme that reduces tumour supportive prostaglandins, and an anti TREM2 antibody designed to alter myeloid cell behaviour.
In preclinical GBM studies, a single injection of the virus extended survival and led to strong activation of T cells, natural killer cells and myeloid cells within the tumour. The researchers say the system represents a safe and traceable oncolytic virus that could finally unlock immunotherapy for patients with GBM, although clinical trials will be required to confirm its effectiveness in humans.
Reference
Giovannoni F et al. Retargeted oncolytic viruses engineered to remodel the tumor microenvironment for glioblastoma immunotherapy. Nature Cancer. 2025; https://doi.org/10.1038/s43018-025-01070-6.
