Research Spotlight: Researchers Develop mRNA Strategy to Turn “Cold” Tumors “Hot”

Riddha Das, PhD, of the Mass General Brigham Center for Systems Biology (CSB), is the co-lead author of a paper published in Nature Biotechnology, “Immune-remodeling mRNAs expressing IRF8 or NIK generate durable anti-tumor immunity in multiple cancer models.” Ralph Weissleder, MD, PhD, and Christopher Garris, PhD, also of the CSB, are the co-senior authors.

Q: What challenges or unmet needs make this study important?

Immunotherapy has transformed cancer care, but it doesn’t work for many patients. One reason is that tumors can create a protective environment that blocks the immune system, often by surrounding themselves with cells that weaken or shut down immune attacks. In particular, these tumors limit the activity of T cells—the immune system’s main cancer-fighting cells—preventing them from recognizing and destroying cancer.

Tumors that respond well to immunotherapy typically already contain active T cells and are often described as “hot.” In contrast, tumors that lack T cells—known as “cold” tumors—are much less likely to respond. Unfortunately, most tumors fall into this cold category. Our work aims to enhance the immune priming of tumors to help turn cold tumors hot for a much more efficient antitumor response.

Q: What central question(s) were you investigating?

T cells are essential for the immune system to eliminate cancer, but they need clear instructions to recognize and attack tumor cells. These instructions are provided by specialized “antigen-presenting” cells, such as macrophages and dendritic cells. Among these antigen-presenting cells (APC), a specialized type of dendritic cell—known as cDC1—plays a central role in activating cancer-fighting T cells. In this work, we boosted the activity of cDC1 cells within tumors to strengthen immune recognition.

Q: What methods or approaches did you use?

We had previously identified two specific targets in cDC1 biology that render these APC much more effective: NF-κB-inducing kinase (NIK) and interferon regulatory factor 8 (IRF8), a transcription factor. The challenge had been to effectively upregulate these targets in APC. In this work, we delivered mRNAs encoding these factors using special lipid nanoparticles.

After conducting a series of experiments to assess the mRNA immunotherapies’ effects on immune cells, we tested their therapeutic effect across multiple cancer models, including metastatic disease. Finally, we combined these mRNAs with cancer and infectious disease antigens to evaluate their potential to enhance both cancer vaccines and vaccines against infectious diseases.

Q: What did you find?

We found that NIK and IRF8 mRNAs expanded and activated cDC1s, recruited additional immune cells, and helped convert poorly T cell-inflamed, “cold” tumors into more immune-active, “hot” environments. This translated into strong tumor control across multiple cancer models. The responses were durable, protected mice from tumor regrowth, and improved the benefit of checkpoint blockade therapy in difficult-to-treat tumors. 

We also found that these mRNAs acted as powerful vaccine enhancers: when combined with cancer antigen mRNA, they generated strong immune responses lasting up to three months and prevented tumor growth in vaccinated mice, while also enhancing responses to influenza and SARS-CoV-2 antigens.

Q: What are the real-world implications, particularly for patients?

Our development of immune remodeling mRNAs could be the first step toward a new class of mRNA medicines that reprogram the immune system from within. Importantly, this approach could help turn poorly inflamed, therapy-resistant tumors into immune-active tumors that are more visible to the immune system. This could be especially important for patients whose tumors do not respond well to current immunotherapies, including immune checkpoint blockade therapy, and may also be relevant for advanced or metastatic disease.

Our work indicates that mRNA-based approaches have the potential to boost immune responses for both personalized neoantigen vaccines and universal cancer vaccines targeting common tumor antigens.

Q: What was your most memorable moment during the study?

The most memorable moment was seeing the vaccine studies, where the immune response lasted up to three months, and vaccinated mice were protected from tumor growth. It was exciting because it showed that these immune remodeling mRNAs were not only boosting the initial response but also helping generate durable immune memory. Seeing vaccinated mice remain protected months later made the impact of the platform feel much more tangible. That was the point where the study felt especially promising for future cancer vaccine applications.

Authorship: In addition to Das, Weissleder and Garris, Mass General Brigham authors include Xinying Ge.

Paper cited: Gupta, A., et al. “Immune-remodeling mRNAs expressing IRF8 or NIK generate durable anti-tumor immunity in multiple cancer models.” Nature Biotechnology. DOI: 10.1038/s41587-026-03115-2

Funding: This work was partly supported by the CSB Discovery Fund, the Karin Grunebaum Cancer Research Foundation, the Department of Defense (HT9425-24-1-0424), and the National Institutes of Health (T32 CA079443).

Disclosures: Patent applications covering aspects of this work have been filed by Daniel G Anderson, Akash Gupta, Kaelan Reed, Riddha Das, Ralph Weissleder and Christopher Garris.