Metabolic and immune crosstalk between cancer-associated fibroblasts and pancreatic cancer cells

Pancreatic cancer, specifically pancreatic ductal adenocarcinoma (PDAC), is notorious for its aggressive nature and dismal prognosis, ranking as a leading cause of cancer-related mortality worldwide. Despite advancements in surgical techniques, chemotherapies, and novel therapeutic approaches, the overall survival rates remain bleak, primarily due to the complex and dynamic tumor microenvironment (TME) which fosters cancer progression and therapeutic resistance. Central to the TME are cancer-associated fibroblasts (CAFs), which exhibit significant heterogeneity and play multifaceted roles in tumor progression, ranging from remodeling the extracellular matrix to modulating immune responses. Recent breakthroughs in single-cell sequencing and spatial omics have unraveled the diverse functional states and spatial organization of various cell types within the TME, including distinct subtypes of CAFs which differ vastly in their influence on pancreatic cancer pathophysiology. This review delves into the intricate interactions between CAFs and pancreatic cancer cells, highlighting how metabolic reprogramming and immune regulation by CAFs contribute to the high malignancy of PDAC. By integrating single-cell and spatial resolution data, we offer new insights into the metabolic crosstalk and immune landscape remodeling driven by CAFs, establishing a foundation for targeting these stromal interactions in therapeutic strategies.