NK Cell-Derived Extracellular Vesicles Function as Immunomodulators to Regulate Breast Cancer Progression by Activating MHC-I Signalling

Although immune checkpoint inhibitors (ICIs) and adoptive T cell therapy have shown success in cancer treatment, these therapies often have limited efficacy in breast cancer patients because these tumours use various mechanisms to evade immune surveillance and elimination; however, the underlying mechanisms remaining unclear. This study revealed that natural killer (NK) cell-derived extracellular vesicles (NK-EVs) can be internalized by breast cancer cells in vitro and exhibit tumour-homing properties in tumour-bearing mice. Proteomic sequencing revealed that treatment with NK-EVs significantly upregulated the expression of major histocompatibility complex (MHC) class I-related proteins, including antigen processing-related transporters (TAP1 and TAP2), transporter associated with antigen processing binding protein (TAPBP, tapasin), immunoproteasome subunits (PSMB9 and PSMB10), and β2-microglobulin (B2M), in breast cancer cells. These proteins are involved in MHC-I synthesis and endogenous peptide processing/presentation by tumour cells. Moreover, MHC-I expression is essential for antigen presentation and T cell-mediated immune responses. NK-EVs upregulated MHC-I expression on the surfaces of breast cancer cells, thus facilitating the recognition and killing of breast cancer cells by CD8 ⁺ T cells. Additionally, an environment with increased MHC-I levels promoted NK cell maturation and enhanced their cytotoxic functions. Finally, in tumour-bearing mice, NK-EVs combined with NK cell therapy inhibited tumour progression and exhibited good safety. These results suggest that similar strategies may be novel therapeutic approaches for treating patients in the clinic. In the future, the combination of NK-EVs with ICIs or adoptive cell therapy may overcome the limitations of currently available breast cancer immunotherapies by performing two functions, namely, directly killing tumour cells and sensitizing immune cells.