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ABSTRACTRecognition of tumor cells by the immune system is a key step in cancer eradication. Melphalan is an alkylating agent routinely used in the treatment of patients with multiple myeloma (MM), but at therapeutic doses it leads to an immunosuppressive state due to lymphopenia. Here, we used a mouse model of MM to investigate the ability of in vivotreatment with low doses of melphalan to modulate natural killer (NK) cell activity, which have been shown to play a major role in the control of MM growth. Melphalan treatment was able to enhance the surface expression of the stress-induced NKG2D ligands RAE-1 and MULT-1, and of the DNAM-1 ligand PVR (CD155) on MM cells, leading to better tumor cell recognition and killing by NK cells, as highlighted by NK cell increased degranulation triggered by melphalan-treated tumor cells. Remarkably, NK cell population was not affected by the melphalan dose used, but rather displayed activation features as indicated by CD107a and CD69 expression. Furthermore, we showed that low doses of melphalan fail to induce tumor cell apoptosis, but promote the in vivoestablishment of a senescent tumor cell population, harboring high levels of the stress-induced ligands RAE-1 and PVR. Taken together our data support the concept of using chemotherapy in order to boost antitumor innate immune responses and report the possibility to induce cellular senescence of tumor cells in vivo.