PPM1L-dependent PD-L1 dephosphorylation orchestrates tumor-type-specific ubiquitin ligase recognition to govern its...

As a powerful clinical strategy for cancer treatment, immune checkpoint blockage targeting the PD-1/PD-L1 axis is frequently hampered by diverse resistance mechanisms. An in-depth elucidation of the molecular mechanisms governing PD-L1 homeostasis is crucial for improving the immunotherapy response rate. Here, we demonstrate that the PPM1L-E3s-SERPINB1 cascade plays a pivotal role in regulating PD-L1 stability. Specifically, PPM1L-modulated phosphorylation status of PD-L1 dictates its recognition by distinct E3 ubiquitin ligases, including ARIH1, RING1, and RNF2, thereby promoting its proteasomal degradation in a cancer type-dependent manner. Furthermore, we identify SERPINB1 as a driver of PD-L1 ubiquitination and degradation, which exerts the function by specifically relieving ARIH1 autoinhibition. Moreover, in mouse models, Ppm1l deficiency exhibits a synergistic antitumor effect with anti-PD-1 immunotherapy. Notably, the expression levels of both PPM1L and SERPINB1 are clinically significant. Collectively, our findings depict a regulatory landscape that governs PD-L1 homeostasis and highlights the significance of precision therapeutic strategies.