taxanes enhance trastuzumabmediated adcc on tumor cells through nkg2dmediated nk cell recognition recent clinical data indicate a synergistic therapeutic effect between trastuzumab and taxanes in neoadjuvantly treated her2positive breast cancer bc patients in her2 bc experimental models and patients we investigated whether this synergy depends on the ability of druginduced stress to improve nk cell effectiveness and thus trastuzumabmediated adcc her2 bc cell lines bt474 and mdamb361 treated with docetaxel showed upmodulation of nk activator ligands both in vitro and in vivo accompanied by a 1540 increase in in vitro trastuzumabmediated adcc antibodies blocking the nkg2d receptor significantly reduced this enhancement nkg2d receptor expression was increased by docetaxel treatment in circulating and splenic nk cells from mice xenografted with tumor cells an increase related to expansion of the cd11bly6g cell population accordingly nk cells derived from her2 bc patients after treatment with taxanecontaining therapy expressed higher levels of nkg2d receptor than before treatment moreover plasma obtained from these patients recapitulated the modulation of nkg2d on healthy donors nk cells improving their trastuzumabmediated activity in vitro this enhancement occurred mainly using plasma from patients with low nkg2d basal expression our results indicate that taxanes increase tumor susceptibility to adcc by acting on tumor and nk cells and suggest that taxanes concomitantly administered with trastuzumab could maximize the antibody effect especially in patients with low basal immune effector cytotoxic activity