Pancreatic Ductal Adenocarcinoma (PDAC) is the fourth leading cause of cancer-related deaths in the United States and is projected to become the second by 2030. PDAC is challenging to treat due to late diagnosis and resistance to therapies. The tumor microenvironment (TME) is a major barrier, characterized by desmoplasia, a dense fibrotic environment that suppresses immune responses and promotes tumor growth. The TME includes cancer cells, stromal cells, immune cells, and an extracellular matrix, creating an immunologically cold environment. This environment is resistant to immune therapies and promotes tumor progression. The TME is influenced by factors such as chronic inflammation, hypoxia, and mutations in genes like KRAS and p53. PDAC cells secrete factors that recruit and activate stromal cells, leading to fibrosis and immune suppression. Pancreatic stellate cells (PSCs) play a key role in fibrosis and tumor progression, contributing to the desmoplastic reaction. Cancer-associated fibroblasts (CAFs) also contribute to the TME, influencing tumor growth, metastasis, and immune suppression. The TME is further influenced by myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs), which suppress immune responses and promote tumor growth. The TME is a complex network of interactions that must be targeted to improve immunotherapy outcomes for PDAC. Understanding the TME is crucial for developing effective therapies for PDAC.Pancreatic Ductal Adenocarcinoma (PDAC) is the fourth leading cause of cancer-related deaths in the United States and is projected to become the second by 2030. PDAC is challenging to treat due to late diagnosis and resistance to therapies. The tumor microenvironment (TME) is a major barrier, characterized by desmoplasia, a dense fibrotic environment that suppresses immune responses and promotes tumor growth. The TME includes cancer cells, stromal cells, immune cells, and an extracellular matrix, creating an immunologically cold environment. This environment is resistant to immune therapies and promotes tumor progression. The TME is influenced by factors such as chronic inflammation, hypoxia, and mutations in genes like KRAS and p53. PDAC cells secrete factors that recruit and activate stromal cells, leading to fibrosis and immune suppression. Pancreatic stellate cells (PSCs) play a key role in fibrosis and tumor progression, contributing to the desmoplastic reaction. Cancer-associated fibroblasts (CAFs) also contribute to the TME, influencing tumor growth, metastasis, and immune suppression. The TME is further influenced by myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs), which suppress immune responses and promote tumor growth. The TME is a complex network of interactions that must be targeted to improve immunotherapy outcomes for PDAC. Understanding the TME is crucial for developing effective therapies for PDAC.