• Posted April 19, 2026

New Clues Explain Why Immunotherapy Fails in Pancreatic Cancer

Immunotherapy has largely failed as a treatment for cancer of the pancreas, and researchers have zeroed in on a key reason.

Pancreatic tumors reprogram immune cells that normally shut down tumor-killing cells, according to a team at Oregon Health & Science University in Portland. 

"Pancreatic cancer is incredibly resistant to most therapies," said senior author Katelyn Byrne, an assistant professor at the OHSU School of Medicine. 

“Even when we know the immune system is capable of long‑lasting protection, it’s been very difficult to get that response to work in this disease,” she added in a news release.

Immunotherapies like immune checkpoint inhibitors have revolutionized treatment of melanoma and lung cancer. But they haven’t shown the same benefit for pancreatic cancer, the third-leading cause of cancer-related death in the U.S.

The presence inside pancreatic tumors of large numbers of regulatory T cells (Tregs) is a big reason why. Simply put, they overtake immune cells capable of killing tumors.

"If there are a lot of them in a tumor, it’s extremely hard to get an anti-tumor immune response going," Byrne said.

She and her team reported this month in the journal Immunity on mouse tests of an experimental immunotherapy. 

Known as agonistic CD40, it works differently from standard checkpoint inhibitors.

Instead of targeting one immune signal, it activates a broader response.

And it didn’t just activate tumor-killing cells, researchers were surprised to find, it converted them into cells that supported anti-tumor activity.

"We didn’t expect this," Byrne said. "Cells that were shutting down the immune reaction suddenly started supporting tumor killing."

The findings help explain why many immunotherapies don’t work in pancreatic cancer and suggest a possible solution. 

Treatments may need to attack with a double-whammy — activating the immune system while overcoming the tumor’s own ability to shut it down.

While results of studies in animals often differ in the humans, these discoveries could be meaningful in treating a disease in which most patients stop responding to available treatments over time, researchers said. 

Combo strategies could make immunotherapy useful, Byrne said.

The research also points to opportunities to combine immune-based treatments with newer cancer drugs, such as KRAS inhibitors, that directly attack pancreatic cancer cells but still rely on immune support.

"You can imagine hitting the cancer cell with a targeted drug while also reprogramming the immune environment around it," Byrne said. "That combination could be much more effective than either approach alone."

Clinical trials using this combo therapy should be underway in humans within the next several years, she said. 

Her lab is now working to better understand the communication between immune cells inside pancreatic tumors and to find out whether the reprogrammed cells offer long-term protection.

More information

There’s more about pancreatic cancer at the Pancreatic Cancer Action Network.

SOURCE: Oregon Health & Science University, news release, April 10, 2026