Novel Strategy Targets Pancreatic Cancer’s Fuel Source to Enhance Treatment Efficacy

New research reveals a promising approach to combat pancreatic cancer by disrupting its reliance on a key nutrient,possibly making existing therapies more effective.

Pancreatic ductal adenocarcinoma (PDAC), a notoriously aggressive cancer, exhibits a unique dependency on glutamine for its energy needs. This reliance, however, creates a vulnerability that scientists are now beginning to exploit. A recent study has uncovered a novel strategy that targets how cancer-associated fibroblasts (CAFs) within the tumor microenvironment acquire nutrients, leading to significant improvements in the effectiveness of immunotherapy and chemotherapy.

Reprogramming the Tumor Microenvironment

The pancreatic cancer tumor microenvironment is a complex ecosystem where cancer cells interact wiht various stromal cells, including CAFs. These CAFs, often characterized as myofibroblasts, play a crucial role in promoting tumor stiffness and density. This physical barrier not only hinders the infiltration of immune cells but also impedes the delivery of therapeutic drugs to the tumor core.

In a groundbreaking revelation, researchers found that by preventing CAFs from utilizing a specific nutrient-scrounging strategy known as macropinocytosis, they could induce a significant shift in the CAF population. This intervention led to a decrease in the myofibroblast subtype and an increase in a different CAF subtype marked by the expression of genes associated with inflammation.

“Most pancreatic CAFs are myofibroblasts that promote stiffness and density in the tumor microenvironment and make it more difficult for immune cells and drugs to reach the tumor,” explained Cosimo Commisso, PhD, senior author and interim director and deputy director of the institute’s cancer center. “Our experiments led to a subtype reprogramming with fewer myofibroblasts and more inflammatory CAFs, and we wondered how this change would affect the overall tumor microenvironment.”

Unlocking Tumor Access and drug Delivery

The consequences of this CAF reprogramming were profound. The research team observed a dramatic alteration in the tumor neighborhood, directly resulting from the inhibition of macropinocytosis in CAFs.

“There were fewer deposits of collagen that make the tumor microenvironment stiff or fibrotic, more access for CD4+ and CD8+ T cells to infiltrate the tumor, and vascular expansion, which means a widening of blood vessels that can promote drug delivery,” stated Zhang, a lead researcher on the study.

This recalibration of the tumor microenvironment effectively dismantled some of the physical barriers that typically shield PDAC from therapeutic intervention. The reduced fibrosis and increased vascularity create a more permissive environment for both immune cells and chemotherapy drugs to reach and attack cancer cells.

Synergistic Effects with Combination Therapies

Building on these findings, the investigators sought to determine if these tumor microenvironment modifications could translate into improved patient outcomes. They tested the efficacy of combining a macropinocytosis inhibitor with established cancer treatments, namely immunotherapy and chemotherapy.The study revealed that combining a macropinocytosis inhibitor, EIPA, with an anti-PD-1 antibody-a type of immunotherapy that targets immune checkpoints-significantly suppressed tumor metastasis and prolonged survival in mice.

“infiltrating T cells are rich in a cell surface protein called PD-1 that dampens the immune response, so we combined a macropinocytosis inhibitor called EIPA with an anti-PD-1 antibody,” Commisso elaborated. “We found it significantly suppressed tumor metastasis and prolonged mouse survival.”

Similarly, using EIPA as a pre-treatment before administering the chemotherapy drug gemcitabine yielded comparable positive results. This combination not only synergistically suppressed tumor growth in mice with PDAC but also effectively reduced the spread of micrometastases to the lungs.

A Promising Avenue for Future Cancer Treatments

The scientists are committed to further exploring strategies that prevent tumors from scavenging energy,with the ultimate goal of reshaping the tumor microenvironment to enhance the effectiveness of cancer treatments.”We believe this is a very promising strategy to pursue for developing combination therapies for cancer patients,” Commisso concluded. “Especially for pancreatic cancer that is the third leading cause of cancer deaths despite accounting for only three percent of cases.”

This research offers a beacon of hope for patients battling pancreatic cancer and potentially other malignancies that rely on similar metabolic pathways. By targeting the fundamental mechanisms that fuel tumor growth and resistance, this novel approach could pave the way for more effective and less toxic cancer therapies.

Source:

ZHANG, Y., et al. (2025). Macropinocytosis maintains CAF subtype identity under metabolic stress in pancreatic cancer. Cancer Cell*. doi.org/10.1016/j.ccell.2025.06.0