Ruthenium complexes boost NK cell immunotherapy via sensitizing triple-negative breast cancer and shaping immuno-microenvironment

Discovery of effective chemical sensitizers to synergize with natural killer cells immunotherapy is urgently desired to overcome its unsatisfactory efficacy in clinic. Herein, we design a series of ruthenium (Ru) polypyridyl complex to systematically explore their potentials in facilitating NK cells treatment. Intriguingly, the chemical structure greatly determines the activity of Ru complexes, while only RuPOP effectively regulates the immuno-suppressors and target proteins within tumor cells. This unique property contributes to its good capability in enhancing the sensitivity of MDA-MB-231 cells to NK cells from cancer patients. Furthermore, besides directly damaging tumor cells, RuPOP pretreatment together with NK cells can also induce robust ROS generation, activate multiple apoptosis-related receptors like TNF-R1, DR5, Fas and maximize the interactions between NK and tumor cells via up-regulating NKG2D and its multiple ligands to trigger caspase 3-dependent apoptosis. Moreover, the combination treatment exhibits high in vivo therapeutic efficacy against breast tumor through boosting the infiltration of NK cells and reducing the protumoral capability of myeloid-derived suppressor cells (MDSC). This study sheds lights for designing metal complexes to potentiate NK cells immunotherapy with clear action mechanisms and provides important information for developing more effective adoptive cell transfer therapy in clinic.