Pancreatic Ductal Adenocarcinoma (PDAC) is the second leading cause of cancer-related deaths in the United States, with limited early detection and treatment options. The tumor microenvironment (TME) plays a crucial role in the therapeutic challenges of PDAC. The desmoplastic environment, characterized by stromal support cells and immunomodulatory cells, creates a physical and immunologic barrier that promotes tumor progression and systemic resistance. Key components of the TME include pancreatic cancer cells (PCCs), pancreatic stellate cells (PSCs), cancer-associated fibroblasts (CAFs), and various immune cells such as myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages (TAMs), and tumor-associated neutrophils (TANs). PCCs release chemokines and cytokines that recruit and activate support cells, leading to increased fibrosis and hypoxia. PSCs, activated by chronic inflammation and hypoxia, produce extracellular matrix proteins that contribute to the dense, fibrotic environment. CAFs, derived from PSCs, exhibit different phenotypes and functions, including myofibroblastic CAFs (myCAFs) and inflammatory CAFs (iCAFs), which play significant roles in tumor progression and chemoresistance. The TME also includes MDSCs, TAMs, and TANs, which contribute to immune suppression and tumor promotion. Understanding the complex interactions between these components and their signaling pathways is essential for developing effective therapeutic strategies to overcome the immunologically cold nature of PDAC.Pancreatic Ductal Adenocarcinoma (PDAC) is the second leading cause of cancer-related deaths in the United States, with limited early detection and treatment options. The tumor microenvironment (TME) plays a crucial role in the therapeutic challenges of PDAC. The desmoplastic environment, characterized by stromal support cells and immunomodulatory cells, creates a physical and immunologic barrier that promotes tumor progression and systemic resistance. Key components of the TME include pancreatic cancer cells (PCCs), pancreatic stellate cells (PSCs), cancer-associated fibroblasts (CAFs), and various immune cells such as myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages (TAMs), and tumor-associated neutrophils (TANs). PCCs release chemokines and cytokines that recruit and activate support cells, leading to increased fibrosis and hypoxia. PSCs, activated by chronic inflammation and hypoxia, produce extracellular matrix proteins that contribute to the dense, fibrotic environment. CAFs, derived from PSCs, exhibit different phenotypes and functions, including myofibroblastic CAFs (myCAFs) and inflammatory CAFs (iCAFs), which play significant roles in tumor progression and chemoresistance. The TME also includes MDSCs, TAMs, and TANs, which contribute to immune suppression and tumor promotion. Understanding the complex interactions between these components and their signaling pathways is essential for developing effective therapeutic strategies to overcome the immunologically cold nature of PDAC.