Gonadotropin-releasing hormone (GnRH) analogs (e.g., triptorelin) are developed to treat hormonedependent reproductive cancers. However, these analogs lack any signi cant direct antitumor activity to make them suitable for hormone-refractory reproductive cancers. In this study, we modi ed GnRH peptide and triptorelin to improve their stability, pharmacokinetic properties, and potency and subsequently broaden their clinical applications in cancer. We investigated biological properties of lipid-modi ed GnRH analogs, with/without D-amino acid substitution at position 6 to yield GnRH-and triptorelin-based derivatives, respectively, in prostate and ovarian cancer cells. We showed that the improved stability due to lipid-modi cation and D-amino acid substitution played a pivotal role in enhancing GnRH receptormediated direct antiproliferative activity (up to 4.5-fold higher than triptorelin) and gonadotropin-releasing potency. Furthermore, sex steroids played signi cant but contrasting roles in regulating the direct antiproliferative activity of the lipopeptides in cancer cells. The superior activity of these GnRH analogs over triptorelin renders promises for developing new GnRH receptor ligands to treat hormone-dependent and -refractory cancers, as well as emerging new targeting moieties for the delivery of anticancer agents in GnRH receptor-overexpressing cancers.