Platinum(IV) Complexes Trigger Death Receptors and Natural Killer Cells to Suppress Breast Cancer

Chemoimmunotherapy is an alternative treatment against cancers. Platinum(IV) complexes FMP and DFMP, coupling formononetin derivative as axial ligand(s), were designed to suppress triple-negative breast cancer (TNBC) by activating death receptors (DRs) and natural killer (NK) cells. These complexes show great potential to overcome the resistance of TNBC to chemotherapy by inducing both intrinsic and extrinsic apoptosis in cancer cells. Particularly, FMP with one axial formononetin derivative not only induced the caspase-3-dependent intrinsic apoptosis but also upregulated the expression of DRs and caspase-8, triggered the extrinsic apoptosis, and enhanced the cytotoxic ability of NK92 cells. Moreover, FMP increased the release of granzyme B, restrained the proliferation and differentiation of myeloid-derived suppressor cells, and the secretion of IL-10, thus inhibiting the TNBC in vitro and in vivo. The results demonstrate that FMP overcomes the chemoresistance and immune escape of TNBC through a new mechanism involving the synergy of chemotherapy and immunotherapy.