The IL-17B/IL-17RB oncogenic signaling axis promotes pancreatic cancer progression through interaction with mixed-lineage kinase 4 (MLK4). Here, we improved the effectiveness of a therapeutic peptide (TAT-IL17RB403–416, loop peptide) that disrupted IL-17RB/MLK4 interaction by converting its linear structure into a cyclic form. The modified cyclic peptide with higher uptake efficiency inhibited pancreatic cancer cell growth and metastasis, outperforming the original linear peptide both in vitro and in an orthotopic mouse model. At the molecular level, cysteine 408 in IL-17RB was important for mediating interactions with arginine 216 within MLK4 kinase domain. This interaction was fundamental to the efficacy of the cyclic peptide. Additionally, lysine 410 in IL-17RB was essential for maintaining the structural integrity of the cyclic peptide as a protein–protein disruptor These findings provide a deeper understanding of the IL-17RB–MLK4 interaction, offering insights for developing therapeutic agents targeting this pathway in pancreatic cancer.