Cancer does not grow in isolation. Tumors live in busy neighborhoods inside the body, surrounded by immune cells, connective tissue, blood vessels, and a mesh of proteins and sugars that give tissues their structure.
Scientists call this neighborhood the “tumor microenvironment.” Just like people rely on their surroundings for food, water, and shelter, cancer cells rely on this microenvironment to get the extra resources they need to grow and spread.
Pancreatic ductal adenocarcinoma, or PDAC, is the most common type of pancreatic cancer and one of the deadliest. This cancer is especially skilled at “fishing” for food in its environment.
It changes its cell surface to grab nutrients from the jelly-like material between cells, called the extracellular matrix. This process is known as macropinocytosis. It allows the cancer to pull in proteins and other molecules to feed itself.
But this “energy fishing” doesn’t just feed the cancer. It also changes the tumor’s surroundings. The connective tissue becomes stiff and dense, making it harder for immune cells to get inside the tumor. This creates a protective barrier for the cancer, helping it avoid attack.
Researchers at the Sanford Burnham Prebys Cancer Center wanted to see what would happen if they blocked macropinocytosis in PDAC. Their study, published in Cancer Cell in July 2025, found that shutting down this process could reshape the tumor’s environment in ways that make cancer treatments more effective.
The team first looked at special connective tissue cells called fibroblasts. Normally, fibroblasts help maintain healthy tissue. But near tumors, some are “reprogrammed” into cancer-associated fibroblasts, or CAFs, which help the cancer grow.
CAFs provide nutrients, send growth signals, and contribute to the dense tissue that blocks treatments and immune cells.
One key nutrient both PDAC cells and CAFs compete for is glutamine, an amino acid that helps build proteins. PDAC is unusually dependent on glutamine, so CAFs often end up starved. When the researchers blocked macropinocytosis in CAFs, the cells couldn’t scavenge for glutamine in the same way.
This caused a shift in CAF types: instead of more stiff tissue-producing myofibroblasts, there were more inflammatory CAFs. These inflammatory CAFs can change the tumor environment to be less of a fortress.
The researchers saw major differences. There was less collagen, which meant the tissue around the tumor was softer. Blood vessels were wider, which could help drugs get in more easily. Most importantly, more immune cells — including CD4+ and CD8+ T cells — were able to infiltrate the tumor.
To see how this could work in treatment, the team combined a macropinocytosis blocker called EIPA with other cancer therapies. When used with an anti-PD-1 immunotherapy drug, the combination slowed tumor spread and helped mice live longer. PD-1 is a protein on T cells that reduces their activity, so blocking it can help the immune system fight cancer.
They also tried giving EIPA before the chemotherapy drug gemcitabine. This not only slowed tumor growth in mice but also reduced tiny cancer spread (micrometastases) in the lungs.
The findings suggest that cutting off the cancer’s scavenging ability could “open up” the tumor, making it more vulnerable to treatment. The researchers believe this strategy could be especially valuable for pancreatic cancer, which causes more deaths than almost any other cancer but makes up only about three percent of all cancer cases.
This study is significant because it targets not just the cancer cells but also the surrounding environment that helps them survive. By stopping the cancer from “fishing” for food through macropinocytosis, the researchers were able to weaken its defenses, making both chemotherapy and immunotherapy more effective.
While these results are in mice and more work is needed before testing in humans, the approach could lead to powerful combination therapies. For a cancer as difficult to treat as PDAC, even small gains in treatment effectiveness could mean longer survival and better outcomes for patients.
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The study is published in Cancer Cell.
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