A new study from the Icahn School of Medicine at Mount Sinai challenges a central assumption in mRNA vaccine biology, showing that immune cells are not the only — or even the primary — determinant of vaccine effectiveness. Instead, non-immune cells such as muscle and liver cells play a previously underappreciated role in shaping immune responses, with major implications for mRNA vaccines and therapeutics.
The preclinical research, published in Nature Biotechnology, also introduces a programmable system that allows scientists to control which cell types express mRNA-encoded proteins. In mouse models, this approach significantly improved the efficacy of an mRNA cancer vaccine for lymphoma.
“This study fundamentally changes how we think mRNA vaccines work,” Brian D. Brown, Director of the Icahn Genomics Institute and senior author of the study, said in the press release. “For years, the field has assumed that getting the mRNA into dendritic cells, the immune cells that activate T cells, was essential. We show that’s not the case. These cells are still important but mRNA delivery to them is not required.”
Rethinking the biology of mRNA vaccines
mRNA vaccines gained widespread recognition during the COVID-19 pandemic after becoming the first mRNA-based vaccines to be deployed at scale, demonstrating both rapid development and strong efficacy. They work by delivering genetic instructions into cells, prompting them to produce a target protein — such as the spike protein of SARS-CoV-2. This protein is then recognized by the immune system, triggering antibody production and activation of T cells.
Using a synthetic control system based on microRNA target sequences, the researchers selectively turned off mRNA expression in specific cell types, including dendritic cells, liver cells, and muscle cells. This allowed them to dissect which cells were truly necessary for immune activation.
Unexpectedly, they found that direct mRNA expression in dendritic cells was not required to generate strong T cell responses — even against SARS-CoV-2 antigens. Instead, other cells were doing much of the work.
Non-immune cells actively shape immune responses
The study shows that non-immune cells help determine whether an mRNA vaccine generates a strong or weak immune response. They found that muscle cells can enhance immune responses by providing additional antigen for immune activation, while liver cells can suppress the response, reducing overall T cell activity. The immune system then relies on dendritic cells to acquire antigen indirectly from these sources, rather than producing it themselves.
These opposing effects suggest that where the mRNA is expressed in the body can be just as important as the antigen it encodes.
This could have broad implications for both mRNA-based vaccines and therapeutics. “We found that hepatocytes actively dampen the immune response to mRNA vaccines,” said Sophia Siu, co-lead author of the study. “This is notable because hepatocytes can take up a lot of mRNA, particularly when it’s injected intravenously. For vaccines, we discovered that we don’t want expression in hepatocytes. However, for mRNA therapeutics, hepatocyte expression can be beneficial because it may help prevent immunity to the mRNA-encoded protein.”
A built-in switch to tune immune responses
The researchers then tested a modified mRNA cancer vaccine in a mouse lymphoma model to see if it affected vaccine performance. They compared a standard mRNA vaccine with one engineered to avoid expression in liver cells.
While both vaccines slowed tumor growth compared with controls, the modified version was significantly more effective, reducing tumor burden by more than half. This improvement was accompanied by a stronger anti-tumour T cell response, with more tumour-infiltrating CD8+ T cells and a higher proportion of cells showing markers of activation and cytotoxic function.
Importantly, these T cells also showed fewer signs of exhaustion, suggesting a more sustained and effective immune response. The findings indicate that liver cell expression of mRNA weakens anti-tumour immune responses, and avoiding expression in the liver can significantly improve mRNA cancer vaccine effectiveness.
“These results show that we can make mRNA cancer vaccines more effective simply by controlling where the mRNA-encoded antigen is expressed,” said Josh Brody, Director of the Lymphoma Immunotherapy Program at Mount Sinai and co-author of the study. “It’s a new lever for improving immunotherapy.”
These findings could influence the design of a wide range of mRNA-based therapies, including gene editing tools like CRISPR, CAR T cell therapies, and treatments for autoimmune and genetic diseases.
A new design principle for mRNA medicine
The ability to dial immune responses up or down depending on which tissues express the mRNA offers a potential framework for improving both efficacy and safety. As mRNA technologies continue to advance, including self-amplifying and more stable formulations, controlling where and how long mRNA is expressed is likely to become increasingly important.
“Our work provides a new set of design rules for mRNA vaccines and therapeutics,” said Brown. “As this technology continues to evolve, understanding and controlling where mRNA is expressed will be critical.”
