Anti-estrogens as hormone therapy are the mainstay treatment for estrogen receptor (ER)-positive breast cancer. ER inhibitors through modulating the transcriptional function of ER have been the frontline anti-estrogens to which refractory phenotype often developed in advanced cancer. The anti-estrogen fulvestrant is currently the only clinically approved pure anti-estrogen which causes ER degradation. However, resistance to fulvestrant still occurs and unfortunately it leaves few choices other than chemotherapy as the later-line treatments to fulvestrant-resistant tumors. Here we show that fulvestrant resistance was accompanied by increased expression of a number of innate immune response genes including the natural killer (NK) cell ligand B7-H6 on the cell surface. In an attempt to overcome the drug resistance phenotype, a NK-based molecular approach taking advantage of a chimeric antigen receptor (CAR) system targeting B7-H6 was established and tested in cells with acquired resistance to fulvestrant. The results demonstrate that the cell therapy approach as a single agent can effectively induce cell death of the resistant cancer cells which is enhanced by the increased expression of cell surface B7-H6. This approach departs from the traditional strategies of conquering anti-estrogen resistant breast cancer and offers a new avenue to eradicate hormone-refractory malignant solid tumors.