Leveraging chemotherapy-induced PD-L1 upregulation to potentiate targeted PD-L1 degradation using nanoparticle-based targeting chimeras

• Published in: Chemical engineering journal (Lausanne, Switzerland : 1996) Switzerland : 1996), 2024-11, Vol.499, p.155708, Article 155708
• Main Authors: Li, Yuai, Wang, Jingwen, Yu, Ruilian, Gong, Tao, Zhang, Zhirong, Liu, Renhe, Fu, Yao
• Format: Article
• Language: English
• Subjects: Chemoimmunotherapy resistance; Combination therapy; Lysosome; PD-L1; Targeted protein degradation
• ISSN: 1385-8947
• DOI: 10.1016/j.cej.2024.155708

•Nanoparticle-based chimera (NanoTACPD-L1) efficiently shuttles PD-L1 to lysosomes for degradation.•The degradation effect of NanoTACPD-L1 does not rely on specific lysosomal-targeting ligand-receptor binding, but is positively correlated with PD-L1 expression levels.•NanoTACPD-L1 can leverage paclitaxel-induced PD-L1 upregulation to intensify PD-L1 degradation.•The combination therapy can effectively combat long-standing chemo-immunotherapy resistance. The combination of nab-paclitaxel and the programmed death-ligand 1(PD-L1) antibody atezolizumab showed limited benefits in clinical trials involving PD-L1-positive triple-negative breast cancer patients. This observed lack of success is attributed to the upregulation of PD-L1 on tumor cells induced by paclitaxel, leading to resistance against PD-L1 antibodies. Here, we introduce nanoparticle-based PD-L1 targeting chimeras (NanoTACPD-L1) to induce PD-L1 degradation instead of blockade. NanoTACPD-L1 initiates endocytosis, independent of specific lysosome-targeting receptors, and delivers membrane-bound PD-L1 to lysosomes for targeted degradation. Furthermore, the efficiency of degradation is directly correlated with the PD-L1 expression level. NanoTACPD-L1 effectively leverages paclitaxel-induced PD-L1 upregulation to enhance PD-L1 degradation, employing a “Meet-Plot-With-Plot” strategy. In a series of in vivo models, NanoTACPD-L1 demonstrates superior therapeutic efficacy and immune activation, both when administered individually and in combination with paclitaxel, surpassing the effects of anti-PD-L1 antibody treatment. Collectively, our study provides a nanotechnology-based tool that can be enhanced by paclitaxel for PD-L1 degradation and validates its potential application in overcoming chemo-immunotherapy resistance.