Targeting microRNA communication reverses pancreatic cancer's immune suppression

In a unique finding, researchers at Georgetown's Lombardi Comprehensive Cancer Center discovered that when pancreatic cancer cells send out tiny particles that are packed with certain microRNA molecules, nearby immune cells called macrophages are reprogrammed to help the tumor grow instead of engaging in their regular role of fighting the tumor. This insight from cell and mouse experiments helped the scientists outline a potential way to reverse the process and possibly improve outcomes in pancreatic cancer.

Our approach focuses on blocking adverse outcomes of microRNA-based communication between pancreatic cancer cells and immune cells. By disrupting these channels of communication, we could reprogram the immune cells and restore their ability to fight cancer, resulting in meaningful reductions in pancreatic tumor growth." 

Amrita Cheema, PhD, professor, Departments of Oncology, Biochemistry, Molecular and Cellular Biology and Radiation Medicine at Georgetown and senior author of the study

The study appears January 16, 2026, in the Nature journal Signal Transduction and Targeted Therapy.

In 2025, there were an estimated 67,440 new cases of pancreatic cancer diagnosed in the U.S. and an estimated 51,980 deaths, making it the third leading cause of cancer deaths in the country with a 5-year survival rate of 13 percent. Incidence of aggressive tumors is increasing, especially in women, and has been linked to diet, lifestyle and obesity.

Pancreatic cancer is deadly, in part, because it creates a tumor environment that weakens the body's natural immune defenses against it. It has shown resistance to many current therapeutic approaches owing to a very dense tissue structure surrounding the tumor and a highly immunosuppressive microenvironment that act as barriers for effective chemotherapy and/or immunotherapy. 

To try to better understand the mechanisms behind this resistance to therapies, Cheema's team focused on tiny particles called extracellular vesicles. While healthy pancreatic cells also release these vesicles, the investigators discovered that only cancer cells send specific information from these vesicles that can actively weaken an immune response.

The researchers found that pancreatic cancer cells pack a specific micro-RNA molecule, called miR-182-5p, into their vesicles. When these vesicles are emitted from a cancer cell, they can be carried to nearby macrophages that normally help destroy harmful cancer cells. When macrophages absorb vesicles packed with miR-182-5p, their behavior changes by switching off immune-activating signals while also turning on pathways that suppress immune responses. As a result of these complex actions, the macrophages stop fighting tumors and instead help them grow. 

Encouragingly, the researchers also showed that blocking miR-182-5p can reverse this process. Using established mouse models of pancreatic cancer, the researchers showed that injecting them with nanoparticles designed to block miR182-5p greatly helped restore the tumor cell killing function of macrophages.

"Our findings show that pancreatic cancer actively rewires macrophages using microRNA as signaling molecules. By targeting those signals, we can restore the immune system's ability to fight the tumor," Cheema says. "Additionally, this approach did not broadly damage healthy cells, suggesting it could be a safer and more targeted strategy than blocking all vesicles released from cancer cells as has been suggested by other studies."

The communication pathway between cancer cells and immune cells that the scientists have elucidated in this study is not unique to pancreatic cancer. Because many tumors use similar messaging systems to evade immune attacks, the researchers' proposed therapeutic strategy could potentially be adapted to treat other types of cancer as well.

One major challenge ahead is to improve delivery of drugs to pancreatic tumors without deleteriously affecting normal cells. Therefore, next steps, according to Cheema, will include developing nanoparticle-based novel delivery systems to selectively target human pancreatic cancer cells. 

"While more research is needed before this approach reaches patients, the findings offer new hope for improving outcomes in pancreatic cancer," says Cheema.

In addition to Cheema, authors at Georgetown include Baldev Singh, Pankaj Gaur, Pritha Bose, Yanjun Zhang, Yaoxiang Li, Zihao Zhang, Jeyalakshmi Kandhavelu, William Klotzbier, Meth Jayatilake, Shivani Bansal, Mohd Farhan, Sunain Deol, Partha P Banerjee, Keith Unger and Seema Gupta. Vivek Verma is at the University of Minnesota, Minneapolis.

A provisional patent application has been filed by the Office of Technology Commercialization at Georgetown University. Along with Cheema, Baldev Singh has been named as a co-inventor. Cheema and her co-authors report having no other personal financial interests related to the study.

This work was partially supported by NIH grant P30-CA051008.