Background

The E6 and E7 oncoproteins of human papillomavirus (HPV) type 16 are continuously expressed in cervical cancer and some head and neck cancers. They are rarely found in normal tissues, making them suitable targets for therapeutic vaccines. However, existing E6/E7 vaccines have shown limited efficacy in clinical trials. This is often because, even if the vaccine increases tumor-specific T cells in the peripheral blood, these cells may not be able to enter the immunosuppressive tumor microenvironment and maintain their function.

Another challenge is the efficiency of antigen processing. Even if mRNA produces E6 and E7 proteins within cells, if these proteins are not sufficiently degraded and presented on MHC class I molecules, the cytotoxic T lymphocyte (CTL) response will be weak. The researchers designed an mRNA vaccine in which ubiquitin (UB), which promotes antigen degradation, was attached to the front of E6/E7, and explored a combination strategy to change the immune barrier within the tumor. The results were published online in the international journal Molecular Therapy Oncology on June 29, 2026. Paper Information

Key Findings

The 'mRNA-UB-E6/E7' developed by the researchers is a structure in which a UB tag is attached to the N-terminus of the HPV16 E6 and E7 antigens. UB is designed to direct the synthesized antigen to the proteasome degradation pathway, increasing the generation of antigen peptides and MHC-I presentation. Indeed, the UB-containing vaccine showed higher antigen-specific immune responses and CTL activity compared to the control mRNA, and also increased the frequency of E7-specific CD8-positive T cells. In an HPV-positive tumor model, single administration improved the anti-tumor effect, but did not completely inhibit the tumor.

To overcome this limitation, the researchers combined the vaccine with mRNA expressing immune-modulatory proteins, programmed cell death protein-1 (PD-1) immune checkpoint inhibitors, liver X receptor (LXR) antagonists, and oncolytic viruses. Among several candidates, only the oncolytic herpes simplex virus 'FusOn-H2' further increased efficacy.

In the FusOn-H2 combination group, the infiltration of CD8-positive T cells into the tumor increased, and CTL activity and interferon-gamma (IFN-γ) production were also enhanced. This is thought to be due to the complementary action of the vaccine expanding E6/E7-specific T cells in the periphery and the oncolytic virus destroying tumor cells, creating an inflammatory environment that helps the influx and function of these cells. The experiment demonstrated that simply increasing the magnitude of the immune response is not enough; effector T cells must reach the tumor and function in situ.

Significance and Outlook

This study presents a strategy that separates and solves the two bottlenecks of therapeutic cancer vaccines. The UB tag enhances antigen processing and systemic T cell induction, and FusOn-H2 alters the tumor microenvironment, which is difficult for immune cells to enter. In particular, the fact that the same improvement was not observed in other combination groups, including PD-1 blockade, reveals that strong peripheral immune responses and immune checkpoint inhibition alone are not sufficient to control all HPV-positive tumors.

However, the study was conducted in an HPV-positive preclinical tumor model. In humans, pre-existing HSV immunity, the location and size of the tumor, the efficiency of viral delivery into the tumor, and neutralizing antibodies resulting from repeated administration may affect the outcome. A delivery method that can be applied to metastatic lesions, where intratumoral injection is difficult, also needs to be solved. Subsequent studies should confirm whether the results are reproducible in other HPV genotypes and in different tumors such as cervical cancer and head and neck cancer, as well as assess toxicity and the optimal order and dose of administration.