College of Biotechnology and Bioengineering, Zhejiang University of Technology, Hangzhou 310032, China.
ACS Appl Mater Interfaces. 2024 Nov 13;16(45):61583-61598. doi: 10.1021/acsami.4c10404. Epub 2024 Oct 31.
Pancreatic ductal adenocarcinoma (PDAC) is a clinically challenging cancer and is often characterized with rich stroma and mutated KRAS, which determines the tumor microenvironment (TME) and therapy response. Turning immunologically "cold" PDAC into "hot" is an unmet need to improve the therapeutic outcome. Herein, we propose a programmable strategy by sequential delivery of pirfenidone (PFD) and nanoengineered KRAS specific inhibitor (AMG510) and gemcitabine (GEM) liposomes. PFD could achieve precise reduction of the extracellular matrix (ECM) by reprogramming pancreatic stellate cells (PSCs). Subsequently, targeting the KRAS-directed oncogenic signaling pathway effectively inhibited tumor proliferation and migration, which sensitized a chemotherapeutic drug and promoted immunogenic cell death (ICD). In preclinical mouse models of PDAC, PFD mediated stromal modulation enhanced the deep penetration of nanoparticles and improved their subsequent performance in tumor growth inhibition. The molecular mechanisms elucidated that the stroma intervention and KRAS signal pathway regulation reshaped the immunosuppression of PDAC and optimized cytotoxic T-cell-mediated antitumor immunity with sustained antitumor memory. Overall, our study provides a practical strategy with clinical translational promise for immunologically cold tumor PDAC treatment.
胰腺导管腺癌（PDAC）是一种具有临床挑战性的癌症，通常具有丰富的基质和突变的 KRAS，这决定了肿瘤微环境（TME）和治疗反应。将免疫“冷”的 PDAC 转化为“热”是改善治疗效果的未满足需求。在此，我们提出了一种可编程策略，通过顺序递delivery 吡非尼酮（PFD）和纳米工程 KRAS 特异性抑制剂（AMG510）和吉西他滨（GEM）脂质体来实现。PFD 可以通过重编程胰腺星状细胞（PSCs）来精确减少细胞外基质（ECM）。随后，靶向 KRAS 定向致癌信号通路有效抑制肿瘤增殖和迁移，这使化疗药物敏感，并促进免疫原性细胞死亡（ICD）。在 PDAC 的临床前小鼠模型中，PFD 介导的基质调节增强了纳米颗粒的深层渗透，并提高了它们随后在肿瘤抑制中的性能。阐明的分子机制表明，基质干预和 KRAS 信号通路调节重塑了 PDAC 的免疫抑制作用，并优化了细胞毒性 T 细胞介导的抗肿瘤免疫，具有持续的抗肿瘤记忆。总的来说，我们的研究为免疫冷肿瘤 PDAC 的治疗提供了一种具有临床转化前景的实用策略。
