Cancer-associated fibroblasts and innate immune cells: orchestrators of the immunosuppressive tumor microenvironment

The tumor microenvironment (TME) represents a complex, dynamic, and heterogeneous system in which stromal and immune elements interact to influence tumor development and mechanisms of immune escape. Within the stromal compartment, cancer-associated fibroblasts (CAFs) have been identified as key mediators of immune regulation in the TME. Emerging evidence indicates that CAFs engage in extensive crosstalk with innate immune cell populations-including myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages (TAMs), tumor-associated neutrophils (TANs), natural killer (NK) cells, mast cells, and dendritic cells (DCs). Through these interactions, CAFs contribute to the establishment and maintenance of an immunosuppressive milieu that supports tumor progression and facilitates immune evasion. This review summarizes the molecular interactions between CAFs and innate immune cells in the TME. It highlights how CAF-derived factors such as IL-6, TGF-β, CXCL12, and CSF-1 regulate immune cell recruitment and polarization, promoting immunosuppression, tumor progression, angiogenesis, and metastasis. Additionally, feedback signals from immune cells further sustain CAF activation, creating a self-reinforcing immunosuppressive microenvironment. Elucidating these multidirectional interactions offers important insights into tumor biology and identifies promising therapeutic avenues. Targeting CAF-associated signaling pathways or interfering with CAF-immune cell communication may help restore anti-tumor immune responses and improve the effectiveness of cancer immunotherapy strategies.