Furthermore, by investigating the impact of hinge (CD8 and IgG4) and TM (CD8 and CD28) on D4 CAR T cells, we discover that IgG4H-CD28TM mediated D4 CAR dimerization, leading to enhanced T-cell signaling and tumor regression in pancreatic cancer models with low antigen density. Here, CD8A is linked to familial pancreatic carcinoma.