We tested this working model further by exchanging C1 domains between DGKα and DGKζ given their key role in T cell activation and the interest in developing isoform-selective inhibitors for cancer immunotherapy.13,27,35,36,49 While type 1 DGK C1 domains were moderately interchangeable as previously reported,12 our findings here showed the tolerability of C1 domain swaps between subtype 1 and 4 appeared to be isoform specific. Here, DGKE is linked to cancer.