Abstract The initial commitment to either the CTL- or Th-lineage is made during thymic development, where thymocytes expressing an MHC class II–reactive TCR commit to the CD4 helper T cell lineage, whereas thymocytes with specificity for MHC class I differentiate into the CD8 CTL lineage. The molecular regulation is controlled by the action and counteraction of transcription factors, such as t ThPOK, which promotes the Th fate and Runx3 which drives the differentiation of MHC class I restricted thymocytes into the CD8 CTL-lineage. This dichotomy persists in the periphery, where ThPOK continues to suppress the cytotoxic fate of MHC class II–restricted CD4+ Th cells. Recently, our team made a major breakthrough and showed that the thymic lineage commitment of CD4 Th cells is not fixed and that mature peripheral CD4+ T cells have the plasticity to lose ThPOK expression. We demonstrated that the loss of Thpok expression and the Th fate coincides with the re-expression of CD8α and the induction of a typical CTL phenotype, including 2B4 and Granzyme B expression and IFN-γ and TNF-α cytokine production. Using an in vitro cytotoxic assay, our lab found that these reprogrammed ThPOK− CD4+ T cells display killer capacities. In a new study we now investigate the role of CD4 CTL in anti-tumor immune surveillance. Using the well-described B16-melanoma tumor model, we demonstrated that in vitro differentiated OVA-specific CD4 CTL display anti-tumor capacity and efficiently killed OVA-expressing B16 tumor cells. This studies on CD4 CTL in the cancer field will not only greatly expand our basic understanding of anti-tumor immunity but it will undoubtedly have major implications for translational research to design new cell therapies to treat devastating cancers.