Pancreatic Cancer Uses Blood-Clotting System to Evade Immune Attack; Targeting May Improve Immunotherapy
Nature study identifies localized immune-protective niches that may offer new targets for immunotherapy
Researchers at the Icahn School of Medicine at Mount Sinai have found that small populations of pancreatic cancer cells can create localized immune-protective niches that shield tumors from immune attack. The finding could open new avenues for making immunotherapy more effective against one of the deadliest forms of cancer.
The findings, published in Nature (10.1038/s41586-026-11002-8), show that a small number of pancreatic cancer cells activate genes that stabilize fibrin, a protein that forms a meshwork involved in blood clotting. The study reveals that cancer cells use this wound-healing system to build a protective environment that prevents cancer-fighting immune cells from reaching pancreatic tumors. In preclinical models, disrupting this protective mechanism slowed tumor growth and improved responses to immunotherapy, pointing to a potential strategy for overcoming pancreatic cancer's resistance to immune-based treatments.
"Pancreatic cancer has remained one of the most difficult cancers to treat because it is exceptionally good at shielding itself from the immune system," said Brian D. Brown, PhD, Mount Sinai Professor of Genetic Engineering, Icahn School of Medicine at Mount Sinai, and senior author of the study. "We found that a surprisingly small population of cancer cells can organize local environments that suppress immune responses and protect not only themselves, but neighboring cancer cells as well. If we can disrupt these protective niches, we may be able to make immunotherapy more effective for patients."
Pancreatic ductal adenocarcinoma is among the deadliest cancers, with a five-year survival rate of about 13 percent. While immunotherapies have transformed treatment for several cancers, they have shown little success against pancreatic cancer because the tumor environment can prevent immune cells from recognizing and attacking cancer cells.
Using advanced spatial genomics technology developed at Mount Sinai called Perturb-map, the research team examined how different genes shape the growth and immune cell neighborhoods of pancreatic cancer cells. The technique allows scientists to visualize competition among tumor cells and their surrounding neighborhoods. This mirrors the heterogeneity found in patient tumors, which is a major reason many cancer treatments fail, including treatments for pancreatic cancer.
The investigators identified two proteins produced by pancreatic cancer cells, PAI1 and PAI2, as key drivers of immune protection. These proteins promote the buildup of fibrin, a protein normally involved in blood clotting and wound healing. The fibrin-rich environment attracts, educates, and retains macrophages, which can prevent cancer-fighting immune cells, including T cells, from reaching the tumor. The findings shed light on how pancreatic cancer can resist immunotherapy and may also help explain why patients with pancreatic cancer are more susceptible to blood-clotting complications such as deep vein thrombosis. The findings suggest that tumors can increase blood clotting while suppressing immune activity.
One of the study's most surprising findings was that these protective niches can be created by only a small fraction of tumor cells. In laboratory models, even when just 5 percent of implanted pancreatic cancer cells produced PAI1, they were able to reshape the surrounding immune environment, increasing immune-suppressing macrophages while reducing the number of activated T cells nearby.
"We discovered that immune suppression isn't spread evenly throughout a pancreatic tumor," said Chiara Falcomatà, PhD, postdoctoral fellow at the Icahn School of Medicine at Mount Sinai and first author of the study. "Instead, small groups of cancer cells create localized neighborhoods that protect themselves and nearby cancer cells from immune attack. Understanding how these protective niches form gives us new opportunities to target them therapeutically."
The researchers also explored whether these immune-protective niches could be disrupted. In multiple preclinical models, removing the genes responsible for producing PAI1 or PAI2, or blocking the pathway with an experimental drug, reduced immune suppression, slowed tumor growth, and significantly improved the effectiveness of anti-PD-1 immunotherapy. Blocking interactions between fibrin and macrophages produced similar results.
Although additional research will be needed before these findings can be translated into treatments for patients, the study identifies several potential therapeutic targets that could eventually be combined with existing immunotherapies to improve outcomes for people with pancreatic cancer.
"Our findings suggest there may be several opportunities to interrupt this pathway," Dr. Brown said. "Whether by targeting the proteins produced by cancer cells, the fibrin-rich environment they create, or the immune cells recruited into these regions, each approach offers a potential strategy for making pancreatic tumors more vulnerable to immune attack."
“Our findings also add to a growing understanding of the connection between the clotting system, wound healing, and macrophage control in many different diseases and even aging,” added Dr. Brown. “This goes beyond cancer. PAI1 levels have a very strong association with aging, and a similar fibrin-macrophage axis has been implicated in neurodegenerative diseases such as Alzheimer’s disease. Developing ways to target this axis may have broad therapeutic applications.”
The research used preclinical models, as well as spatial transcriptomics and imaging analysis of patient tumors. Further studies will be necessary to determine whether targeting this pathway is safe and effective in people with pancreatic cancer.
Full study: https://www.nature.com/articles/s41586-026-11002-8
About the Icahn School of Medicine at Mount Sinai
The Icahn School of Medicine at Mount Sinai is internationally renowned for its outstanding research, educational, and clinical care programs. It is the sole academic partner for the seven member hospitals* of the Mount Sinai Health System, one of the largest academic health systems in the United States, providing care to New York City’s large and diverse patient population.
The Icahn School of Medicine at Mount Sinai offers highly competitive MD, PhD, MD-PhD, and master’s degree programs, with enrollment of more than 1,200 students. It has the largest graduate medical education program in the country, with more than 2,700 clinical residents and fellows training throughout the Health System. The Graduate School of Biomedical Sciences offers 12 degree-granting programs, conducts innovative basic and translational research, and trains more than 470 postdoctoral research fellows.
Ranked 11th nationwide in National Institutes of Health (NIH) funding, the Icahn School of Medicine at Mount Sinai is among the 90th percentile of U.S. private medical schools in Sponsored Programs Direct Expenditures per Principal Investigator, according to the Association of American Medical Colleges. More than 6,900 scientists, educators, and clinicians work within and across dozens of academic departments and multidisciplinary institutes with an emphasis on translational research and therapeutics. Through Mount Sinai Innovation Partners (MSIP), the Health System facilitates the real-world application and commercialization of medical breakthroughs made at Mount Sinai.
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* Mount Sinai Health System member hospitals: The Mount Sinai Hospital; Mount Sinai Brooklyn; Mount Sinai Morningside; Mount Sinai Queens; Mount Sinai South Nassau; Mount Sinai West; and New York Eye and Ear Infirmary of Mount Sinai.
About the Mount Sinai Health System
Mount Sinai Health System is one of the nation’s leading integrated academic health systems and one of the largest in the New York metropolitan area. Its comprehensive system includes seven hospitals, more than 400 outpatient practices, over 600 research and clinical laboratories, the Icahn School of Medicine at Mount Sinai, the Graduate School of Biomedical Sciences, and the Mount Sinai Phillips School of Nursing. Together, the Health System comprises approximately 48,000 employees, more than 9,000 physicians, and 8,600 nurses.
As a leading learning health system, Mount Sinai combines clinical expertise with scientific discovery to improve patient care while training the next generation of health care and biomedical leaders. The Health System provides care across every stage of life, from prenatal care through geriatrics, while advancing personalized medicine through artificial intelligence, data science, and biomedical research.
Mount Sinai is consistently recognized among the nation’s leading academic health systems for patient care, research, and education. The Mount Sinai Hospital is ranked No. 1 in New York by Newsweek and No. 5 on the magazine’s World’s Best Hospitals list. The Icahn School of Medicine at Mount Sinai ranks No. 11 among U.S. medical schools and No. 1 among freestanding medical schools for National Institutes of Health funding, reflecting the strength of its scientific enterprise and leadership in biomedical research.