Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer-related morbidity and mortality in the western world, with limited therapeutic strategies and dismal long-term survival. Cancer-associated fibroblasts (CAFs) are key components of the pancreatic tumor microenvironment, maintaining the extracellular matrix, while also being involved in intricate crosstalk with cancer cells and infiltrating immunocytes. Therefore, they are potential targets for developing therapeutic strategies against PDAC. However, recent studies have demonstrated significant heterogeneity in CAFs with respect to their origins, spatial distribution, and functional phenotypes within the PDAC tumor microenvironment. Therefore, it is imperative to understand and delineate this heterogeneity prior to targeting CAFs for PDAC therapy.

Pancreatic cancer is a major cause of cancer-associated mortality globally, characterized by a poor prognosis and limited therapeutic response. The current approach for treating pancreatic cancer involves locoregional control with surgical resection and systemic therapy in the form of cytotoxic chemotherapy. However, despite standard-of-care treatment, the outcomes remain dismal. Emerging evidence suggests that the gut microbiota plays a significant role in pancreatic carcinogenesis through dysbiosis, chronic inflammation and immune modulation. Dysbiosis-driven alterations in the gut microbiota composition can disrupt intestinal homeostasis, promote systemic inflammation and create a tumor-permissive microenvironment in the pancreas. Moreover, the gut microbiota modulates the efficacy of systemic therapies, including chemotherapy and immunotherapy, by impacting drug metabolism and shaping the tumor immune landscape. This review is mainly focused on exploring the intricate interplay between the gut microbiota and pancreatic cancer, and also highlighting its dual role in carcinogenesis and the therapeutic response.