New Immune Pathway Could Supercharge mRNA Cancer Vaccines

A surprising backup system in the immune response to mRNA vaccines may hold the key to more effective cancer treatments.

The arrival of mRNA vaccines against SARS-CoV-2 in 2020 marked a turning point in the COVID-19 pandemic. Today, this Nobel Prize-winning technology is being adapted for cancer treatment. Researchers are testing mRNA vaccines in clinical trials for melanoma, small cell lung cancer, bladder cancer, and other diseases, raising new possibilities for prevention and therapy.

For years, scientists believed that a single type of immune cell was essential for mRNA vaccines to activate the immune system. However, a new mouse study from researchers at Washington University School of Medicine in St. Louis challenges that idea. Even without this key cell type, the vaccine still produced strong cancer-fighting effects. The team discovered that a related immune cell can step in to trigger anti-tumor activity, a surprising result since this cell type does not usually respond to other vaccines.

Rethinking Immune Cell Roles in mRNA Vaccines

The study, published in Nature, provides new insight into how mRNA vaccines interact with the immune system and may help guide the design of more effective cancer vaccines.

"There is a lot of interest in applying the mRNA vaccine approaches used during the COVID-19 pandemic to the problem of inducing anti-tumor immunity," said senior author Kenneth M. Murphy, MD, PhD, the Eugene Opie Centennial Professor of Pathology & Immunology at WashU Medicine. "By dissecting which immune cells are involved and how they coordinate the response, we're offering vaccine developers some additional mechanistic insights to consider in their goal of optimizing these vaccines against tumor proteins."

Murphy is also a research member at Siteman Cancer Center, based at Barnes-Jewish Hospital and WashU Medicine.

Unconventional immune pathway

mRNA vaccines deliver genetic instructions that tell cells to produce small protein fragments. These fragments alert the immune system, which then targets and destroys cells carrying them. Dendritic cells create these protein pieces, while T cells identify and eliminate the affected cells. In cancer vaccines, the proteins are designed to match tumor-specific markers so that T cells can focus on cancer cells.

One dendritic cell type, called cDC1, is known for activating T cells against virus-infected cells. But scientists have not fully understood how T cells are triggered after mRNA vaccination. To investigate, Murphy and his team worked with co-corresponding author William E. Gillanders, MD, the Mary Culver Professor of Surgery at WashU Medicine. Using mouse models that lacked either cDC1 cells or a related subtype called cDC2, they examined how each group contributes to T cell activation.

Gillanders, a physician-scientist and surgical oncologist, also treats patients at Siteman Cancer Center and has developed an experimental vaccine for triple-negative breast cancer.

The researchers found that mice given an mRNA vaccine still developed strong T cell responses even without cDC1 cells. These mice were also able to eliminate sarcoma tumors, which form in connective tissues such as fat, muscle, nerves, blood vessels, bone, and cartilage. This suggested that another cell type was driving the immune response.

A Unique Mechanism of Activation

The study showed that cDC2 cells also help activate T cells and limit tumor growth. T cells activated by cDC1 and cDC2 cells displayed slightly different molecular "fingerprints," which could be useful for improving future vaccine designs.

Mice lacking cDC2 cells, as well as mice with both cell types, were still able to mount immune responses and reject tumors. This indicates that mRNA vaccines can rely on either dendritic cell subtype to generate anti-cancer effects.

Further experiments revealed that cDC2 cells activate T cells through an indirect process. Instead of producing protein fragments themselves, they depend on other cells to process the mRNA instructions, break the proteins into pieces, and display them on their surface. These prepared fragments are then transferred to cDC2 cells through a known process called "cross-dressing," allowing cDC2 cells to engage T cells.

"This work uncovers a new way mRNA vaccines engage the immune system — through both cDC1 and cDC2 — which helps explain their power and gives researchers concrete targets for making future mRNA cancer vaccines more effective," said Gillanders. "It could improve vaccine formulation and dosing, potentially explain why some patients respond better to vaccines than others and guide strategies for making vaccines more effective."

Reference: "mRNA vaccines engage unconventional pathways in CD8+ T cell priming" by Suin Jo, Lijin Li, Chandrani Thakur, Kevin A. Telfer, Hussein Sultan, Ray A. Ohara, Michelle He, Giri Nam, Jing Chen, Feiya Ou, Monia Draghi, Nicholas M. Valiante, Robert D. Schreiber, Gwendalyn J. Randolph, Naresha Saligrama, Theresa L. Murphy, William E. Gillanders and Kenneth M. Murphy, 15 April 2026, Nature.
DOI: 10.1038/s41586-026-10353-6

Funding: National Institutes of Health