Yuan Sichen, Yang Xicheng, Bremmer Alexa M, Wang Yixin, Li Sherry, Chen Yu, You Yawen, Hu Quanyin
Pharmaceutical Sciences Division, School of Pharmacy, University of Wisconsin-Madison, Madison, WI 53705.
Carbone Cancer Center, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53705.
Proc Natl Acad Sci U S A. 2025 Aug 26;122(34):e2507711122. doi: 10.1073/pnas.2507711122. Epub 2025 Aug 19.
Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer with limited treatment options due to its desmoplastic and immunosuppressive tumor microenvironment (TME), which impedes drug delivery and limits T cell infiltration. Immune checkpoint blockade (ICB) has shown poor efficacy in PDAC, partly due to the desmoplastic stroma and low immunogenicity. Peptidyl-prolyl cis/trans isomerase NIMA-interacting 1 (Pin1) promotes both fibrosis and immune evasion, making it a compelling target for TME remodeling. Here, we develop a dual-action, programmable immunoprobiotic delivery system (EcN@Nbs-NP@API-1) that combines Pin1 inhibition with PD-L1 blockade to enhance immunotherapy. This system uses Nissle 1917 (EcN) to selectively deliver nanoparticles encapsulating the Pin1 inhibitor API-1 to PDAC, enabling sustained release to degrade the fibrotic stroma and upregulate PD-L1 on tumor cells, promoting immune infiltration. Engineered EcN also produces anti-PD-L1 nanobodies in situ, synergizing with API-1 to boost CD8 T cell-mediated immunity. In orthotopic PDAC mouse models, this strategy remodels the TME, enhances immune cell infiltration, and improves antitumor response while minimizing systemic toxicity. Moreover, it shows efficacy in other ECM-rich tumors, such as triple-negative breast cancer, highlighting its broader potential. This work presents a promising platform to overcome immunotherapy resistance in solid tumors.
胰腺导管腺癌（PDAC）是一种侵袭性很强的癌症，由于其促结缔组织增生和免疫抑制性肿瘤微环境（TME），治疗选择有限，这种微环境会阻碍药物递送并限制T细胞浸润。免疫检查点阻断（ICB）在PDAC中显示出较差的疗效，部分原因是促结缔组织增生性基质和低免疫原性。肽基脯氨酰顺/反异构酶NIMA相互作用蛋白1（Pin1）促进纤维化和免疫逃逸，使其成为TME重塑的一个有吸引力的靶点。在这里，我们开发了一种双作用、可编程的免疫益生菌递送系统（EcN@Nbs-NP@API-1），该系统将Pin1抑制与PD-L1阻断相结合以增强免疫治疗。该系统利用Nissle 1917（EcN）将包裹Pin1抑制剂API-1的纳米颗粒选择性递送至PDAC，实现持续释放以降解纤维化基质并上调肿瘤细胞上的PD-L1，促进免疫浸润。工程化的EcN还能原位产生抗PD-L1纳米抗体，与API-1协同作用以增强CD8 T细胞介导的免疫。在原位PDAC小鼠模型中，该策略重塑TME，增强免疫细胞浸润，并改善抗肿瘤反应，同时将全身毒性降至最低。此外，它在其他富含细胞外基质的肿瘤（如三阴性乳腺癌）中也显示出疗效，突出了其更广泛的潜力。这项工作提出了一个有望克服实体瘤免疫治疗耐药性的平台。
