由于促纤维增生基质由癌症相关成纤维细胞（CAF）构成，很少有免疫细胞浸润胰腺导管腺癌（PDAC）。加巴喷丁可以阻止 CAF 产生酮酸来支持癌细胞。然而，在我们的研究中，我们发现癌细胞中转化生长因子 β1 (TGF-β1) 水平随加巴喷丁的反应呈剂量依赖性增加。 TGF-β1 的这种反向增加会导致“加巴喷丁耐药”，导致 PDAC 细胞系的抗肿瘤作用在胰腺星状细胞存在的情况下产生负面影响。吡非尼酮与加巴喷丁联用可协同抑制 PDAC 的生长和凋亡抵抗。在小鼠原位 PDAC 模型中，含有加巴喷丁、吡非尼酮和天然多酚 (EGCG) 的 Fe3 介导的配位纳米药物，有效促进幼稚 CD8 T 细胞 (CD44lowCD62Lhigh) 的浸润和炎症 CAF (α-SMAlowIL-6high) 的积累）。与对照组相比，这导致存活率增加了近两倍。此外，在用我们的纳米药物治疗后，我们发现了一个新的亚群 Hmox1highiCAF。 Hmox1highiCAF 过表达 Cxcl10 受体 (Sdc4)，并促进功能性 CD8 T 细胞通过 Tnfsf9-Tnfrsf9 轴浸润。总体而言，我们的纳米药物重塑了 CAF 的表型并增强了功能性 CD8 T 细胞对肿瘤的浸润，有可能成为 PDAC 的安全且有前途的疗法。版权所有 © 2024 作者。由 Elsevier B.V. 出版。保留所有权利。

Owing to the desmoplastic stroma constituted by cancer-associated fibroblasts (CAFs), few immune cells infiltrate the pancreatic ductal adenocarcinoma (PDAC). Gabapentin can impede the production of ketoacids by CAFs to support cancer cells. However, in our study, we discovered a dose-dependent increase in transforming growth factor β1 (TGF-β1) levels in cancer cells in response to gabapentin. This reverse increase of TGF-β1 contributes to 'Gabapentin-resistance', leading to the antitumor effects on PDAC cell lines are negatively negotiated in the presence of pancreatic stellate cells. Pirfenidone synergistically inhibited the growth and apoptosis resistance of PDAC when combined with Gabapentin. In a mouse orthotopic PDAC model, Fe3+-mediated coordination nanodrugs, which contain gabapentin, pirfenidone and the natural polyphenol (EGCG), efficiently promoted the infiltration of naïve CD8+ T cells (CD44lowCD62Lhigh) and the accumulation of inflammatory CAFs (α-SMAlowIL-6high). This led to a nearly two-fold increase in survival compared to the control. Furthermore, we identified a new subpopulation as Hmox1highiCAFs following treatment with our nanodrugs. Hmox1highiCAFs overexpressed the Cxcl10 receptor (Sdc4) and facilitated functional CD8+ T-cell infiltration through the Tnfsf9-Tnfrsf9 axis. Overall, our nanodrugs reshape the phenotype of CAFs and enhance functional CD8+ T-cell infiltration into tumors, holding the potential to be a safe and promising therapy for PDAC.Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.