Oncolytic viruses (OVs) represent a cutting-edge approach in cancer immunotherapy, characterized by their ability to selectively infect and destroy tumor cells by inducing immunogenic cell death and triggering an anti-tumor immune response, without affecting healthy cells. Of the different OVs, HSV-1 shows promising clinical applications due to its potent oncolytic ability, broad infectivity range, ease of genetic manipulation, induction of long-term cellular immune response, and the availability of drugs to control its proliferation.

In a recent review in Genes & Diseases, researchers from the Second Affiliated Hospital of Kunming Medical College, Kunming Institute of Zoology, Chinese Academy of Sciences, and University of the Chinese Academy of Sciences explore the molecular mechanisms underlying HSV glycoprotein-mediated cell entry, the recent advances in receptor-retargeted oHSV-1 engineering, while highlighting the challenges and future directions in the development of oncolytic HSV-based therapies.
Viral entry into the cells differs with cell types. Differences in receptor expression levels and affinities across cell types determine the specific entry pathways used by HSV-1.

This review describes the mechanisms of HSV-1 cell entry, including (i) the direct virion-cell fusion pathway, (ii) the endocytic pathway, and (iii) pathways mediated by specific glycoproteins and their receptors (e.g., glycoprotein C, glycoprotein D, the HSV fusogen gB, and glycoprotein gH/gL).

The review then details the strategies employed for the tropism retargeting of oHSV-1. Conditional replication of oHSV-1 limits viral replication in non-replicating cells while enabling replication in tumor cells to achieve targeted tumor destruction. This is achieved by genetically modifying the virus, primarily by inserting mutations or deletions in viral replication regulatory genes, such as UL39 and UL23, which endow oHSV-1 with tumor-specific cytotoxicity through various mechanisms. Similarly, multi-gene knockout and transcriptional reprogramming are other strategies to engineer oHSV-1 with conditional replication, selective tumor targeting, and safety.

An alternative approach to oHSV-1 retargeting involves redirecting viral tropism to cancer-specific receptors while detargeting natural receptors, enhancing cancer specificity without requiring gene deletions. This strategy involves modifying glycoproteins gD, gH, and gB, which play a major role in viral entry. Previous reports have reported the successful retargeting against a range of tumor-associated receptors, including IL13Rα2, uPAR, GFRα1, HER2, EGFR, PSMA, and EGFRvIII, enabling selective infection of breast cancer, ovarian cancer, and brain tumor cells.

Despite progress in engineering tumor-targeted oHSV-1 with improved specificity and efficacy, off-target effects and alternative entry routes remain challenges, necessitating synergistic modifications across multiple glycoproteins. Future development must focus on integrating advanced gene editing and immunotherapy, alongside dual-layered regulation—combining glycoprotein-based retargeting with tumor-specific replication control—to enhance safety, specificity, and efficacy against metastatic cancers.

In conclusion, integrating innovative glycoprotein engineering, advanced gene editing, and immunotherapy may help bridge the gap between experimental therapeutics and clinical application, positioning oHSV-based therapies as a potential candidate for treating metastatic and refractory cancers.

Reference
Title of the original paper: Engineering HSV-1 for oncolytic therapy: From molecular entry mechanisms to retargeting strategies

Journal: Genes & Diseases
Genes & Diseases is a journal for molecular and translational medicine. The journal primarily focuses on publishing investigations on the molecular bases and experimental therapeutics of human diseases. Publication formats include full length research article, review article, short communication, correspondence, perspectives, commentary, views on news, and research watch.

DOI: https://doi.org/10.1016/j.gendis.2025.101797

Funding Information:

• National Natural Science Foundation of China (No. 82260486, 82173014)
• Yunnan Revitalization Talent Support Program (China)
• Yunnan Medical Discipline Leader Training Project (China)
• Graduate Innovation Fund of Kunming Medical University, Yunnan, China (No. 2024S086)
• Biomedical Projects of Yunnan Key Science and Technology Program (China) (No. 202302AA310046)

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