CD1-restricted T cells specific for self-lipids could play a role in cancer immune surveillance, where self-antigens are the targets of immune responses. We showed that primary acute myelogenous (AML) and B-lymphoblastic (B-ALL) leukemia blasts express CD1c and are recognized by a group of CD1c self-reactive T cells specific for methyl-lysophosphatidic acids (mLPAs), a novel class of self-lipid antigens that accumulate in malignant cells, which control leukemia growth in vitro and in vivo. These findings point to CD1c and self-lipids as new potential targets for leukemia immunotherapy. The little polymorphism of CD1 molecules and their expression on mature leukocytes are indeed highly attractive for adoptive cell therapy (ACT) with such T cells in the context of stem cell transplantation for hematological malignancies. To assess the feasibility of ACT for acute leukemia with mLPA-specific T cells, we generated a library of lentiviral vectors encoding a panel of human mLPA-specific TCRs. Upon TCR transduction, either Jurkat T cells or human primary T cells were specifically retargeted against CD1c-expressing malignant targets in vitro, highlighting a lead mLPA-specific TCR suitable for adoptive immunotherapy. Primary T cells transduced with this TCR killed CD1c-expressing malignant targets in vitro and significantly delayed leukemia progression in NSG mice. To gain further insight into the efficacy and safety of mLPA-specific ACT, we generated transgenic mice expressing CD1c with a pattern similar to the human one, which harbored functional APCs recognized by mLPA-specific T cells and selected a CD1c self-reactive peripheral T cell repertoire. Leukemia immunotherapy by lipid-specific T cells is currently investigated in the CD1c Tg mice with two T cell models: (I) retrogenic mice bearing a monoclonal T cell population expressing the human lead mLPA-specific TCR; and (II) transferred peripheral T cells engineered with the same TCR.