Researchers at Oregon Health & Science University have uncovered a key reason why immunotherapy has largely failed in pancreatic cancer - and identified a promising strategy to overcome that resistance.
The study, published in the journal Immunity, shows that pancreatic tumours actively reshape their immune environment by co‑opting regulatory immune cells that normally shut down tumour-killing cells. By reprogramming those cells, the research reveals a potential pathway to make immunotherapy effective against one of the deadliest and most treatment‑resistant cancers.
“Pancreatic cancer is incredibly resistant to most therapies,” said the study’s senior author, Katelyn Byrne PhD, Assistant Professor of Cell, Developmental and Cancer Biology in the Oregon Health & Science University (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.”
Immune checkpoint inhibitors and other immunotherapies have transformed care for cancers such as melanoma and lung cancer, but they have shown little benefit for pancreatic cancer. One major reason, Byrne said, is the presence of large numbers of regulatory T cells, or Tregs, inside pancreatic tumours.
“Tregs are very suppressive immune cells,” Byrne said. “If there are a lot of them in a tumour, it’s extremely hard to get an anti‑tumour immune response going.”
In many pancreatic cancers, these regulatory cells overtake immune cells capable of killing tumours, effectively neutralising immunotherapy before it can work. In the new study, Byrne and team tested an experimental immunotherapy in mouse models known as agonistic CD40, which works differently from standard checkpoint inhibitors. Rather than targeting a single immune signal, the therapy broadly activates the immune response upstream.
Byrne said the researchers were surprised to find out that activating the immune system this way didn’t just stimulate tumour‑killing cells - it also reprogrammed regulatory T cells, converting them from immune suppressors into cells that support anti‑tumour activity.
“We didn’t expect this,” Byrne said. “The therapy doesn’t directly target T-regs, but as a secondary effect of turning on the immune response, those T-regs changed their behaviour. Cells that were shutting down the immune reaction suddenly started supporting tumour killing.”
The team’s findings help explain one reason why many immunotherapies haven’t worked in pancreatic cancer and point to a possible solution: treatments may need to both turn on the immune system and overcome the tumour’s own ability to shut it down. This could be especially significant for pancreatic cancer, where most patients eventually stop responding to available treatments. Combination strategies could finally make immunotherapy viable, Byrne says.
The research also creates opportunities to combine immune‑based treatments with newer cancer‑targeted drugs, such as KRAS inhibitors, which directly attack pancreatic cancer cells but still rely on immune support for durable responses.
The study also highlights the importance of patient‑specific immune differences. Some pancreatic tumours contain many immune cells that are suppressed by Tregs, while others lack immune cells altogether - suggesting that no single therapy will work for every patient.
Byrne said clinical trials in humans using this combination therapy should be underway within a few years. Her laboratory is now working to further map the complex communication between immune cells inside pancreatic tumours and to determine whether the reprogrammed cells provide long‑term immune protection.
- Maltez VI, Arora C, Gribbin KP, et al. Agonistic anti-CD40 antibody treatment converts resident regulatory T cells into activated type 1 effectors within the tumour microenvironment. Immunity. 2026 Apr 2:S1074-7613(26)00122-6. doi:10.1016/j.immuni.2026.03.011 Online ahead of print.