TOX2 is a transcriptional regulator belonging to the TOX high mobility group box family that functions as a key controller of immune cell differentiation and development. In natural killer (NK) cells, TOX2 promotes maturation by directly upregulating TBX21 (T-BET) expression, a critical transcription factor for NK cell differentiation 1. TOX2 also plays a distinct role in CAR T cell therapy by promoting central memory T cell (TCM) differentiation, contrasting with its paralogue TOX which drives T cell exhaustion 2. During human fetal immune development, TOX2+ precursor cells transition to mature naive CD4+ T cells, indicating involvement in immune system maturation 3. In pathological contexts, TOX2 is aberrantly overexpressed in natural killer/T-cell lymphoma (NKTL), where it functions as an oncogene downstream of RUNX3, promoting cell proliferation and tumor formation through the PRL-3 effector pathway 4. In acute T-cell leukemia, TOX2 nuclear-cytosol translocation, mediated by Sirt1 and TBK1, represses TIM3 transcription through recruitment of the corepressor LCOR and deacetylase HDAC3, contributing to leukemogenesis 5. These findings establish TOX2 as a pleiotropic transcriptional regulator with distinct roles in normal lymphocyte development versus malignant transformation.