Boosting Natural Killer Cell-Based Cancer Immunotherapy with Selenocystine/Transforming Growth Factor-Beta Inhibitor-Encapsulated Nanoemulsion

Natural killer (NK) cell-based immunotherapy represents a promising strategy to overcome the bottlenecks of cancer treatment. However, the therapeutic efficacy is greatly limited by downregulation of recognition ligands on the tumor cell surface, and the immunosuppressive effects can be thwarted by the tumor microenvironment such as secretion of transforming growth factor-beta (TGF-β), which could stunt the NK cell-mediated immune response. To overcome these limitations, herein we developed a nanoemulsion system (SSB NMs) to co-deliver TGF-β inhibitor and selenocysteine (SeC) to achieve amplified anticancer efficacy. SSB NMs significantly enhanced the lytic potency of NK92 cells by 2.1-fold. Moreover, a subtoxic dose of SSB NMs effectively sensitized MDA-MB-231 triple-negative breast cancer (TNBC) cells to NK cells derived from seven clinical patients, resulting in an up to 13.8-fold increase in cancer lysis. Mechanistic studies reveal that the sensitizing effects relied on natural killer group 2, member D (NKG2D)/NKG2D ligands (NKG2DLs) signaling with the involvement of DNA damage response. SSB NMs also effectively restrained TGF-β/TGF-β RI/Smad2/3 signaling, which thus enhanced NKG2DL expression on tumor cells and stimulated NKG2D surface expression on NK92 cells, ultimately contributing to the enhanced immune response. Furthermore, SSB NMs sustained release of SeC and TGF-β inhibitor and synergized with NK92 cells to induce significant anticancer effects in vivo. Together, this study not only demonstrates a simple strategy for the design of a nanoemulsion to co-deliver synergistic drugs but also sheds light on the application and action mechanisms in NK cell adaptive therapy against breast cancer, especially TNBCs.