Innovative Approach: Blocking Fuel Intake Reverses Pancreatic Tumor Environment for Better Treatment Outcomes

Cancer development does not occur in isolation; tumors interact dynamically with their surrounding microenvironment, which includes immune cells, connective tissue, blood vessels, and a matrix of proteins and carbohydrates that provide structural support. Recent research highlights how pancreatic ductal adenocarcinoma (PDAC) cells exploit this environment to fuel their growth through a process called macropinocytosis, where they scavenge nutrients from the extracellular matrix. This activity results in a stiffer connective tissue and impedes immune cell infiltration, contributing to resistance against therapies.

A groundbreaking study by the Sanford Burnham Prebys Cancer Center, published in Cancer Cell on July 24, 2025, reveals that inhibiting macropinocytosis can dramatically alter the tumor microenvironment. By blocking this cellular scavenging, the surrounding stroma becomes less fibrous, blood vessels expand, and immune cells such as CD4+ and CD8+ T lymphocytes gain better access to the tumor site. These modifications significantly improve the efficacy of immunotherapy and chemotherapy in mouse models of PDAC.

The researchers observed that fibroblasts present in the microenvironment, which normally produce extracellular matrix components, are coerced into a tumor-supportive subtype known as cancer-associated fibroblasts (CAFs). These CAFs support tumor growth by supplying metabolites and growth signals. Notably, inhibiting macropinocytosis stressed these CAFs metabolically, leading to a shift from a myofibroblast subtype—responsible for tissue stiffness—to an inflammatory subtype that fosters immune activation.

Further experiments demonstrated that combining a macropinocytosis inhibitor, EIPA, with immune checkpoint blockade (anti-PD-1 antibodies) or chemotherapy (gemcitabine) significantly suppressed tumor growth and metastasis, notably reducing lung micrometastases. This approach enhances immune infiltration and drug delivery, offering a promising therapeutic strategy for pancreatic cancer, which remains a leading cause of cancer-related deaths despite accounting for only a small percentage of cases.

Ongoing research aims to refine this strategy, with the goal of transforming the tumor microenvironment into one more receptive to existing therapies and improving outcomes for patients with pancreatic and other metabolically dependent cancers.