A groundbreaking discovery is challenging everything scientists thought they knew about how mRNA vaccines work, with major implications for treating skin cancer and other malignancies. Researchers at the Icahn School of Medicine at Mount Sinai found that the key to making mRNA cancer vaccines more effective isn't about getting the vaccine into immune cells, as previously believed, but rather about controlling where the vaccine is expressed throughout the body.

Why Do Liver Cells Matter More Than Immune Cells?

For years, immunologists assumed that delivering mRNA directly to dendritic cells, the immune cells responsible for activating cancer-fighting T cells, was essential for vaccine success. The new research overturns this assumption entirely. Instead, the team discovered that non-immune cells, particularly liver cells and muscle cells, play a surprisingly powerful role in determining whether an mRNA vaccine succeeds or fails.

The researchers used a novel technology involving microRNA target sites to selectively "turn off" mRNA expression in specific cell types. When they silenced the vaccine in liver cells, the T cell response tripled compared to traditional mRNA vaccines. Conversely, when they turned off expression in muscle cells, the immune response weakened. This discovery revealed that liver cells actively suppress the immune response to mRNA vaccines, while muscle cells amplify it.

"We found that hepatocytes actively dampen the immune response to mRNA vaccines. 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," said Sophia Siu, an MD/PhD student at the Icahn School of Medicine at Mount Sinai and co-lead author of the study.

Sophia Siu, MD/PhD Student, Icahn School of Medicine at Mount Sinai

How Does This Change Cancer Treatment?

The implications for cancer patients are significant. In mice with lymphoma, an mRNA vaccine engineered to avoid expression in liver cells led to more than a 50 percent reduction in tumor burden compared to traditional mRNA vaccines. This improvement occurred because the hepatocyte-silenced vaccine generated more killer T cells, the immune cells that directly attack cancer.

The findings provide a new framework for designing mRNA vaccines that could work across multiple cancer types. While the current research focused on lymphoma, the underlying immune mechanisms are conserved across species and likely to translate to human patients.

"These results show that we can make mRNA cancer vaccines more effective simply by controlling where the mRNA-encoded antigen is expressed. It's a new lever for improving immunotherapy," explained Josh Brody, MD, Director of the Lymphoma Immunotherapy Programme at the Mount Sinai Tisch Cancer Centre.

Josh Brody, MD, Director of the Lymphoma Immunotherapy Programme, Mount Sinai Tisch Cancer Centre

Ways to Improve Immunotherapy Response in Melanoma

Beyond mRNA vaccine design, researchers are pursuing multiple strategies to help more melanoma patients benefit from immunotherapy. A separate research initiative funded by the American Cancer Society is investigating how the tumor microenvironment helps cancer cells hide from the immune system.

• Targeting Dendritic Cell Dysfunction: Researchers are studying how specific immune cells called type 2 conventional dendritic cells (cDC2s) shape the immune response to melanoma. Understanding how these cells become dysfunctional in tumors could reveal new ways to restore anti-tumor immunity.
• Controlling the Innate Immune System: The innate immune system, which we're born with, serves as the first line of defense against cancer. By identifying mechanisms that control innate immune responses, scientists can develop therapies that work alongside existing immunotherapies to enhance survival.
• Blocking Tumor Immune Evasion: Cancers evade detection through multiple mechanisms, including immune cell exclusion and production of immunosuppressive molecules. New therapies aim to disrupt these evasion tactics and restore the body's ability to recognize and destroy cancer cells.

Fred Hutch Cancer Center researcher Kevin Barry, PhD, is leading one such investigation with a $270,000 grant from the American Cancer Society. His team will focus on understanding how tumors manipulate the innate immune system to block protective immune responses, with the goal of developing novel immunotherapies that enhance patient survival.

"While melanoma or MSI-high colorectal patients have the best chance of responding to these treatments, a large proportion of patients even in these responsive indications don't benefit. Our immune system protects against cancer, and the new immunotherapies work by re-activating the immune system to kill cancer and, in some cases, essentially cure patients," said Kevin Barry, PhD, a molecular biologist at Fred Hutch Cancer Center.

Kevin Barry, PhD, Molecular Biologist, Fred Hutch Cancer Center

What's the Current State of Immunotherapy for Skin Cancer?

Immunotherapy has become one of the four major pillars of cancer treatment, alongside surgery, radiation, and chemotherapy. For some patients, it can provide lifelong protection against cancer recurrence. However, the reality is sobering: only about 30 percent of patients respond to immunotherapy overall, and even in melanoma, where response rates are highest at 37 percent, most patients still don't benefit.

This gap between potential and reality is why researchers are investigating the fundamental mechanisms of how tumors evade immune detection. Melanoma was chosen as the focus for much of this research because it has the longest history with immunotherapy, making it an ideal model for understanding how to improve outcomes.

"In order to develop immunotherapies that fully harness the power of the immune system to fight cancer, it's imperative to understand how tumors evade the immune system," noted Kevin Barry, PhD.

Kevin Barry, PhD, Molecular Biologist, Fred Hutch Cancer Center

The Mount Sinai research team plans to continue developing their mRNA technology to improve treatments for solid organ cancers and to explore how the same principles could be used to create mRNA vaccines for autoimmune diseases. By understanding and controlling where mRNA is expressed in the body, scientists are opening new possibilities for precision medicine in cancer care.

"The ability to tune the immune response up or down is incredibly powerful. We now have both a conceptual framework and a practical technology to do that," said Brian D. Brown, PhD, senior author of the study and Director of the Icahn Genomics Institute.

Brian D. Brown, PhD, Director of the Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai