Rational development of gemcitabine-based nanoplatform for targeting SERPINB9/Granzyme B axis to overcome chemo-immune-resistance

作者：Haozhe Huang, Yiqing Mu, Yixian Huang, Beihong Ji, Yifei Wang, Chien‐Yu Chen, Yuang Chen, Zhangyi Luo, Sihan Li, Sihan Li, Ziqian Zhang, Luxuan Wang, James F. Conway, Junmei Wang, Junmei Wang, Jingjing Sun, Song Li, Song Li · 发表于：Nature Communications · 年份：2025 · DOI：10.1038/s41467-025-59490-y · 被引用次数：10 · 研究领域：Phagocytosis and Immune Regulation、RNA Interference and Gene Delivery、PARP inhibition in cancer therapy

SERPINB9, an endogenous inhibitor of granzyme B (GzmB), has emerged as a critical factor in the resistance to immunotherapy by protecting cancer cells from GzmB-induced cytotoxicity. However, its role in chemosensitivity remains unknown. In this study, we show that gemcitabine (GEM) treatment upregulates SERPINB9 through transcription factor ATF-3. Interestingly, GEM also induces the expression of GzmB and knockout or knockdown of SERPINB9 results in enhanced response of tumor cells to GEM, suggesting a role of GzmB/SERPINB9 axis in regulating chemosensitivity. To facilitate the therapeutic translation of these findings, we engineer POEM nanocarrier (consisting of lipid-derivatized polylysine (PEG-PLL-Oleic acid, PPO), and GEM-conjugated polylysine (PEG-PLL-OA-GEM, PPOGEM), PPO/PPOGEM (POEM)) that is highly effective in codelivery of built-in GEM and loaded SERPINB9 short interfering RNA (siSPB9). GEM conjugation introduces an additional mechanism of carrier/siRNA interaction in addition to charge-mediated interaction and enables efficient i.v. delivery at lower N/P ratios. Here, we show that co-delivery of GEM and siSPB9 significantly improves antitumor efficacy and remodels the tumor immune microenvironment in pancreatic cancer models, supporting a promising therapeutic strategy. SERPINB9 (SPB9) has been reported as a critical factor in the resistance to immunotherapy but its role in chemosensitivity remains unknown. Here this work reports that gemcitabine (GEM) treatment l...