Unraveling the Role of Cancer-Associated Fibroblasts in Natural Killer Cell Immunosuppression in Breast Cancer

Cancer-associated fibroblasts (CAFs) are among the most abundant components of the breast tumor microenvironment and are key players in immune modulation. They regulate various immune cells, including T-cells, macrophages, and dendritic cells, but their interaction with natural killer (NK) cells—crucial for anti-tumor immunity—remains underexplored. In this short talk, we will present our findings from multiple mouse models of breast cancer, ex-vivo co-cultures and in-vivo modeling to demonstrate NK cell-mediated surveillance of CAFs. We will unravel the mechanisms behind this suppression, focusing on ligand-receptor interactions that lead to CAF cytolysis and downregulation of activating receptors on NK cells, thereby enabling cancer cells to evade NK cell surveillance. Additionally, we will present data from triple-negative breast cancer patients, showing the accumulation of NK cells in CAF-rich regions and the upregulation of NK-binding ligands on CAFs, which correlate with poorer disease outcomes. These insights reveal a CAF-mediated immunosuppressive decoy mechanism, underscoring significant implications for the treatment of solid tumors.