Decoding the Intricate Landscape of Pancreatic Cancer: Insights into Tumor Biology, Microenvironment, and Therapeutic Interventions

Abstract

Pancreatic ductal adenocarcinoma (PDAC) presents significant oncological challenges due to its aggressive nature and poor prognosis. The tumor microenvironment (TME) plays a critical role in progression and treatment resistance. Non-neoplastic cells, such as cancer-associated fibroblasts (CAFs) and tumor-associated macrophages (TAMs), contribute to tumor growth, angiogenesis, and immune evasion. Although immune cells infiltrate TME, tumor cells evade immune responses by secreting chemokines and expressing immune checkpoint inhibitors (ICIs). Vascular components, like endothelial cells and pericytes, stimulate angiogenesis to support tumor growth, while adipocytes secrete factors that promote cell growth, invasion, and treatment resistance. Additionally, perineural invasion, a characteristic feature of PDAC, contributes to local recurrence and poor prognosis. Moreover, key signaling pathways including Kirsten rat sarcoma viral oncogene (KRAS), transforming growth factor beta (TGF-β), Notch, hypoxia-inducible factor (HIF), and Wnt/β-catenin drive tumor progression and resistance. Targeting the TME is crucial for developing effective therapies, including strategies like inhibiting CAFs, modulating immune response, disrupting angiogenesis, and blocking neural cell interactions. A recent multi-omic approach has identified signature genes associated with anoikis resistance, which could serve as prognostic biomarkers and targets for personalized therapy.

Keywords: Notch signaling; PD-L1; TGF-beta signaling; cancer-associated fibroblasts; macrophages; pancreatic cancer; tumor microenvironment; tumor-associated macrophages.

Figure 1

Schematic representation of the pancreatic ductal adenocarcinoma (PDAC) tumor microenvironment (TME). In normal pancreatic tissue, stromal cells such as fibroblasts play a supportive role in tissue homeostasis and repair. However, cancer-associated fibroblasts (CAFs) are activated and secrete a variety of factors that promote tumor growth and invasion. CAFs contribute to the dense desmoplastic stroma that is a hallmark of pancreatic cancer, which can limit the delivery of chemotherapy drugs to the tumor.