Intrapancreatic Fat, Pancreatitis, and Cancer: Role of Cancer-Associated Fibroblasts

Introduction

Pancreatic diseases, including pancreatitis and pancreatic ductal adenocarcinoma (PDAC), represent a significant global health burden due to their aggressive nature and poor prognosis. Emerging research highlights the critical role of intrapancreatic fat (IPF) in promoting chronic inflammation, fibrosis, and carcinogenesis. Additionally, the dynamic interactions between pancreatic cancer cells and cancer-associated fibroblasts (CAFs) further drive tumor progression, therapy resistance, and metastasis. This review explores the interplay between IPF, pancreatitis, and PDAC, with a focus on how CAFs contribute to disease pathogenesis and potential therapeutic targeting.

Intrapancreatic Fat: A Metabolic Driver of Pancreatic Pathology

Excessive fat accumulation within the pancreas, known as intrapancreatic fat or pancreatic steatosis, has been linked to metabolic disorders such as obesity and type 2 diabetes. IPF contributes to local inflammation by releasing free fatty acids and pro-inflammatory cytokines, creating a microenvironment conducive to pancreatic injury. In chronic pancreatitis, IPF exacerbates fibrosis by activating pancreatic stellate cells (PSCs), which differentiate into myofibroblasts and deposit excessive extracellular matrix (ECM) proteins. This fibrotic milieu not only impairs pancreatic function but also establishes a pre-malignant niche that facilitates the development of pancreatic cancer.

From Pancreatitis to Pancreatic Cancer: The Inflammatory-Fibrotic Cascade

Chronic pancreatitis is a well-established risk factor for PDAC, with persistent inflammation driving genetic mutations (e.g., KRAS, TP53) and epigenetic alterations. IPF amplifies this process by promoting oxidative stress and acinar-to-ductal metaplasia (ADM), a precursor to pancreatic intraepithelial neoplasia (PanIN). As inflammation progresses, activated PSCs and immune cells secrete growth factors (TGF-β, PDGF) and cytokines (IL-6, TNF-α), further stimulating fibrogenesis and creating a tumor-permissive stroma. The transition from pancreatitis to cancer is thus marked by a shift from acute injury repair to dysregulated proliferation and stromal remodeling.

Cancer-Associated Fibroblasts: Architects of the Pro-Tumorigenic Niche

CAFs are a dominant stromal component in PDAC, originating from PSCs, resident fibroblasts, and bone marrow-derived cells. These cells play a dual role—while initially attempting to restrain tumor growth, they eventually become co-opted by cancer cells to support invasion and immune evasion. CAFs secrete ECM proteins (collagen, fibronectin) that stiffen the tumor microenvironment (TME), impairing drug delivery and promoting hypoxia. Additionally, they release exosomes and signaling molecules (SDF-1, HGF) that enhance cancer cell survival, stemness, and metastatic potential.

CAF-Cancer Cell Crosstalk: Mechanisms of Therapy Resistance

A key challenge in PDAC treatment is the profound desmoplastic reaction mediated by CAFs, which creates a physical and biochemical barrier against chemotherapy and immunotherapy. Cancer cells exploit CAF-derived signals (such as Wnt and SHH pathways) to sustain proliferation and evade apoptosis. Furthermore, CAF-induced immunosuppression—via recruitment of regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs)—limits the efficacy of immune checkpoint inhibitors. Recent studies suggest that CAF heterogeneity (inflammatory vs. myofibroblastic subtypes) influences tumor behavior, offering new avenues for stroma-targeted therapies.

Therapeutic Strategies: Targeting IPF and CAFs in Pancreatic Cancer

Given the pivotal role of IPF and CAFs in PDAC progression, several therapeutic approaches are under investigation. Anti-fibrotic agents (such as pirfenidone and halofuginone) aim to reduce stromal density and improve drug penetration. Metabolic interventions, including lipid-lowering drugs and PPAR-γ inhibitors, may mitigate IPF-driven inflammation. Additionally, CAF-directed therapies—such as FAP-targeted CAR-T cells and FAK inhibitors—seek to disrupt tumor-stroma interactions. However, challenges remain due to the paradoxical tumor-suppressive effects of certain CAF subsets, necessitating precision stromal modulation.

Conclusion

The interplay between intrapancreatic fat, chronic pancreatitis, and pancreatic cancer underscores the importance of metabolic and stromal factors in disease pathogenesis. CAFs serve as central mediators of tumor progression, shaping an immunosuppressive and fibrotic TME that resists conventional therapies. Future research should focus on stratifying CAF subtypes and developing combinatorial strategies that simultaneously target cancer cells, stromal components, and metabolic dysregulation. By unraveling these complex interactions, we may pave the way for more effective treatments for this lethal malignancy.

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