['The MHC-unrestricted activity of cytokine-induced killer (CIK) cells against chemo-surviving melanoma cancer stem cells (mCSCs) was explored, as CSCs are considered responsible for chemo-resistance and relapses.', 'Putative mCSCs were visualized by engineering patient-derived melanoma cells (MCs) with a lentiviral-vector encoding eGFP under expression control by stemness gene promoter oct4. Their stemness potential was confirmed in vivo by limiting dilution assays. We explored the sensitivity of eGFP+mCSCs to chemotherapy (CHT), BRAF inhibitor (BRAFi) or CIK cells, as single agents or in sequence, in vitro. First, we treated MCs in vitro with fotemustine or dabrafenib (BRAF-mutated cases); then surviving MCs, enriched in mCSCs, were challenged with autologous CIK cells. CIK cell activity against chemoresistant mCSCs was confirmed vivo in two distinct immunodeficient murine models.', 'We visualized eGFP+mCSCs (14±2.1%) in 11 MCs. The tumorigenic precursor rate in vivo was higher within eGFP-positive MCs (¼2) compared with the eGFP-negative counterpart (¼870). In vitro mCSCs were relatively resistant to CHT and BRAFi, but killed by CIK cells (n=11, 8/11 autologous), with specific lysis ranging from 95% (E/T 40:1) to 20% (E/T 1:3). In vivo infusion of autologous CIK cells into mice bearing xenografts from 3 distinct melanoma demonstrated significant tumor responses involving CHT-spared eGFP+mCSCs (p=0.001). Sequential CHT-immunotherapy treatment retained antitumor activity (n=12, p=0.001) reducing mCSC rates (p=0.01).'] Do cytokine Induced Killer cells kill chemo-surviving melanoma cancer stem cells?