胰腺导管腺癌（PDAC）在具有独特pH环境的器官中发展，其中结缔组织在每餐后酸化。我们假设在PDAC进展过程中干扰这种pH环境会触发胰腺星状细胞（PSCs）和癌相关成纤维细胞（CAFs）引发PDAC纤维化。我们揭示碱性环境pH足以诱导PSC分化为肌成纤维样表型。然后，在机械上解析这一发现，重点研究钠/氢交换体NHE1的参与。通过使用cariporide抑制NHE1扰乱细胞pH稳态，部分改变了肌成纤维细胞样PSC表型。为了展示这一发现在体内的相关性，我们针对小鼠PDAC（KPfC）靶向NHE1。确实，当小鼠同时接受NHE1抑制剂cariporide和吉西他滨治疗时，肿瘤纤维化减轻。此外，肿瘤免疫浸润从富含粒细胞转变为更多的淋巴细胞。综上所述，我们的研究提供了关于胰腺pH环境如何通过调节PSC分化来塑造胰腺癌的机制证据。

Pancreatic ductal adenocarcinoma (PDAC) progresses in an organ with a unique pH landscape, where the stroma acidifies after each meal. We hypothesized that disrupting this pH landscape during PDAC progression triggers pancreatic stellate cells (PSCs) and cancer-associated fibroblasts (CAFs) to induce PDAC fibrosis. We revealed that alkaline environmental pH is sufficient to induce PSC differentiation to a myofibroblastic phenotype. We then mechanistically dissected this finding focusing on the involvement of the Na+/H+ exchanger NHE1. Perturbing cellular pH homeostasis by inhibiting NHE1 with cariporide partially alters the myofibroblastic PSC phenotype. To show the relevance of this finding in vivo, we targeted NHE1 in murine PDAC (KPfC). Indeed, tumor fibrosis decreases when mice receive the NHE1-inhibitor cariporide in addition to gemcitabine treatment. Moreover, the tumor immune infiltrate shifts from granulocyte-rich to more lymphocytic. Taken together, our study provides mechanistic evidence on how the pancreatic pH landscape shapes pancreatic cancer through tuning PSC differentiation.