Employing methylcholanthrene (MCA)-induced sarcoma as well as MC38 colon adenocarcinoma model systems and human NR2F6 knockdown T-cell cultures as well as analyzing tumor-infiltrating lymphocytes (TIL) in human NSCLC biopsy samples, we here provide strong pre-clinical evidence that upregulation of NR2F6 at the tumor site renders effector T cells incapable of mounting sufficient anti-cancer immune response. Here, NR2F6 is linked to colon adenocarcinoma.