Mechanical Insights into Immunosuppression in Pancreatic Ductal Adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy, which is characterised by an immunosuppressive tumour microenvironment (TME) that leads to poor responses to immunotherapies. Here, we discuss recent advances in our understanding of the PDAC TME and provide a comprehensive overview of both tumour cell-intrinsic and extrinsic factors that contribute to immune evasion in PDAC. The roles of tumour intrinsic factors in remodelling the TME and promoting tumour progression will be discussed, which includes mutations in KRAS and activation of pathways such as IL-6/STAT3, Wnt/-Catenin and NF-B. Moreover, based on the pre-clinical and research evidence, we depict the immune landscape within the PDAC TME and highlight the dynamic reciprocal interaction between tumour cells and various immune cell populations. Also, we outline the impact of non-immune cells, particularly pancreatic stellate cells (PSCs), cancer-associated fibroblast (CAFs) and adipocytes in shaping an immunosuppressive TME. Finally, we explore how metabolic reprogramming and altered nutrient dynamics within the TME further enhance immunosuppression. Understanding these interconnected mechanisms offers promising avenues for novel therapeutic strategies that target the immunosuppressive landscape of PDAC.