The advent of mRNA vaccines against SARS-CoV-2 in 2020 changed the course of the COVID-19 pandemic. This Nobel Prize-winning technology is now being applied in the fight against cancer, with mRNA vaccines being tested in clinical trials against melanoma, small cell lung cancer and bladder cancer, among others, opening the door to new ways to prevent and treat the disease.
Scientists hypothesized that mRNA vaccination requires one specific immune cell subtype to activate the immune system. But researchers at Washington University School of Medicine in St. Louis have shown in a new study in mice that even in the absence of these cells, mRNA vaccines elicit a strong cancer cell-killing response. That’s because they discovered that cousins of this immune cell subtype can also stimulate anti-tumor immune activity. This is an unexpected finding given that this related subtype has not been implicated in responses to other vaccines.
The findings will be published on April 15th. natureto better understand how the immune system responds to mRNA vaccination and guide the optimal design of cancer vaccines.
There is a lot of interest in applying the mRNA vaccine approach used during the COVID-19 pandemic to the problem of inducing antitumor immunity. Analyzing which immune cells are involved and how they coordinate responses is providing vaccine developers with additional mechanistic insights to consider in their goal of optimizing vaccines against tumor proteins. ”
Kenneth M. Murphy, MD; senior writer, Eugene Opie Centennial Professor of Pathology and Immunology at WashU Medicine
Murphy is also a research member of the Siteman Cancer Center, based at Barnes-Jewish Hospital and WashU Medicine.
Unconventional immune pathways
mRNA vaccines are in the form of messenger RNA biomolecules that instruct immune cells to produce fragments of proteins, triggering the immune system to destroy cells that carry these proteins. So-called dendritic cells produce protein fragments from mRNA instructions that are searched for and destroyed by another immune cell, T cells. mRNA vaccines can be designed to produce tumor-specific protein bits so that T cells can eliminate these cancer cells.
cDC1, the classical type 1 dendritic cell, have long been known to be effective teachers that stimulate T cells to attack virus-infected cells. However, little is known about how T cells are activated after mRNA vaccination, whether against viruses or tumors. In collaboration with study co-corresponding author William E. Gillanders, MD, and Mary Culver, professor of surgery at WashU School of Medicine, Murphy and members of his lab used a mouse model lacking related cell subtypes known as cDC1 or cDC2 to uncover the role that different groups of dendritic cells play in priming T cells after mRNA cancer vaccination.
Dr. Gillanders is a physician-scientist and surgical oncologist who is also involved in the development of an investigational vaccine for triple-negative breast cancer and treats patients at the Cytoman Cancer Center.
As part of the study, scientists found that mice immunized with the mRNA vaccine generated strong T cell responses even in the absence of cDC1. They also discovered that immunized mice lacking cDC1 were able to eliminate sarcoma tumors (cancers that develop in connective tissues such as fat, muscle, nerves, blood vessels, bone, and cartilage). This indicates that other cell types must be stimulating the T cell response.
In fact, their study found that cDC2 is also involved in generating immune responses from T cells and preventing tumor growth. The study also found that T cells turned on by cDC1 and cDC2 each exhibited slightly different molecular “fingerprints.” These differences could help scientists design better versions of vaccines in the future.
Similarly, immunized mice lacking cDC2 and mice with both cell subtypes mounted an immune response and rejected tumor growth, demonstrating that mRNA vaccination harnesses both dendritic cell subtypes to block cancer.
Further investigation of cDC2 suggested that cDC2 activates T cells through an outsourced process that relies on other cells to use mRNA instructions to make a protein, chop it up, and present small pieces on its surface. Once the proteins are processed and presented, these cells transfer membrane complexes that hold the fragments in place on the cell surface to cDC2s, where they bind to T cells through a known process called “cross-dressing.”
“This study reveals a new way in which mRNA vaccines engage the immune system through both cDC1 and cDC2. This helps explain their power and provides researchers with concrete targets to make future mRNA cancer vaccines more effective,” Professor Gillanders said. “It could improve vaccine formulation and dosing, explain why some patients respond better to vaccines than others, and guide strategies to make vaccines more effective.”
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Reference magazines:
Yes, Mr. S. Others. (2026). mRNA vaccines engage a non-conventional pathway in priming CD8+ T cells. nature. DOI: 10.1038/s41586-026-10353-6. https://www.nature.com/articles/s41586-026-10353-6
