Abstract: Fusion polypeptides with modified multimerization domains that provide high expression, solubility, stability, and low immunogenicity to the fusion polypeptides have been developed. TRAIL compositions with the modified multimerization domains show improved physico-chemical and biological properties relative to TRAIL compositions with unmodified multimerization domains. The TRAIL compositions also have lower immunogenicity in the mammalian host when compared to that of TRAIL compositions with unmodified multimerization domains. The TRAIL compositions induce apoptosis of cancer cells and cancer-associated fibroblasts in vivo, reducing tumor size.