Data from either in vitro IL-2 differentiation or murine models of cancer seem to suggest that while TBET (and associated Th1 functions such as IFN-γ secretion) may be dispensable for cytotoxic CD4+ T cell generation and function, whether EOMES or BLIMP-1 is important may depend on the specific conditions and disease context; while it is noted that TBET and RUNX3 are critical for generation of cytotoxic CD4+ IELs, it is unclear how this may generalize to cytotoxic CD4+ T cells in human cancer. This evidence concerns the gene RUNX3 and cancer.