Blocking nutrient scavenging in pancreatic cancer reshapes the tumor environment, making it more vulnerable to immunotherapy and chemotherapy. A new study from Sanford Burnham Prebys demonstrates that disrupting how cancer cells steal resources from their surroundings dramatically improves treatment outcomes in mice. The findings, published in Cancer Cell, highlight a promising strategy for overcoming resistance to existing therapies, particularly in aggressive cancers like pancreatic ductal adenocarcinoma (PDAC).
How Cancer Cells Hijack Their Surroundings
Pancreatic tumors aggressively consume nutrients from the extracellular matrix through a process called macropinocytosis. This essentially allows cancer cells to scavenge for sustenance, reinforcing their growth while simultaneously hardening the tissue around them and preventing immune cells from reaching the tumor. This creates a fortified environment that traditional therapies struggle to penetrate.
Researchers discovered that blocking macropinocytosis in cancer-associated fibroblasts (CAFs) — cells that support tumor growth — leads to metabolic stress. CAFs, typically starved of glutamine in PDAC tumors, are forced into a different state. This shift results in a reduction of collagen deposits, which make tumors dense and difficult to treat.
Reprogramming the Tumor Microenvironment
The key finding is that starving CAFs alters the tumor’s structure. Blocking macropinocytosis causes the tumor microenvironment to become less fibrous, increasing access for immune cells (CD4+ and CD8+ T cells) and expanding blood vessels to improve drug delivery.
“Our experiments led to a subtype reprogramming with fewer myofibroblasts and more inflammatory CAFs,” said Dr. Cosimo Commisso, senior author of the study. “We wondered how this change would affect the overall tumor microenvironment.”
The resulting shift in the tumor’s neighborhood allows treatments to work more effectively. When combined with immunotherapy (anti-PD-1 antibodies) or chemotherapy (gemcitabine), blocking macropinocytosis significantly suppressed tumor growth, reduced metastasis, and prolonged survival in mice.
Implications for Human Treatment
These results suggest a new approach to cancer therapy: depriving tumors of essential nutrients to weaken their defenses. By reshaping the tumor microenvironment, clinicians may be able to enhance the efficacy of existing treatments, particularly in cancers that rely heavily on scavenging like pancreatic cancer. The study suggests that combination therapies that include macropinocytosis inhibitors could offer a significant advantage.
The researchers are now focused on refining this strategy for human trials, with the goal of developing more effective treatments for cancer patients. Pancreatic cancer remains the third leading cause of cancer deaths despite accounting for only three percent of cases, underscoring the urgency of finding new therapeutic approaches.
