胰腺导管腺癌（PDAC）细胞中，糖酵解得到了高度增强，因此在PDAC肿瘤微环境（TME）中对非肿瘤细胞施加了葡萄糖限制。然而，目前对于这种葡萄糖竞争如何改变代谢并在TME中赋予基质细胞表型变化几乎一无所知。在这里，我们报告称具有受限葡萄糖可用性的癌相关成纤维细胞（CAFs）利用来自糖酵解增强的癌细胞的乳酸作为燃料，并在PDAC TME中发挥免疫抑制活性。乳酸脱氢酶A（LDHA）的表达，它调控乳酸的生成，是PDAC患者的不良预后因素，LDHA耗竭抑制了CAF丰富的小鼠PDAC模型的肿瘤生长。CAF与PDAC细胞的共培养显示大部分葡萄糖被肿瘤细胞吸收，而CAF通过单羧酸转运体1通过TCA循环消耗乳酸以增强增殖。此外，乳酸刺激的CAF上调了IL6的表达，并与乳酸协同抑制细胞毒性免疫细胞活性。最后，LDHA抑制剂FX11减少了CAF丰富的PDAC肿瘤的生长，并改善了反肿瘤免疫。我们的研究为糖酵解产生的乳酸介导的肿瘤细胞、CAF和免疫细胞之间的相互作用提供了新的见解，并提供了针对PDAC细胞中LDHA酶活性的治疗策略。

Glycolysis is highly enhanced in Pancreatic ductal adenocarcinoma (PDAC) cells; thus, glucose restrictions are imposed on nontumor cells in the PDAC tumor microenvironment (TME). However, little is known about how such glucose competition alters metabolism and confers phenotypic changes in stromal cells in the TME. Here, we report that cancer-associated fibroblasts (CAFs) with restricted glucose availability utilize lactate from glycolysis-enhanced cancer cells as a fuel and exert immunosuppressive activity in the PDAC TME. The expression of lactate dehydrogenase A (LDHA), which regulates lactate production, was a poor prognostic factor for PDAC patients, and LDHA depletion suppressed tumor growth in a CAF-rich murine PDAC model. Coculture of CAFs with PDAC cells revealed that most of the glucose was taken up by the tumor cells and that CAFs consumed lactate via monocarboxylate transporter 1 to enhance proliferation through the TCA cycle. Moreover, lactate-stimulated CAFs upregulated IL6 expression and suppressed cytotoxic immune cell activity synergistically with lactate. Finally, the LDHA inhibitor FX11 reduced tumor growth and improved antitumor immunity in CAF-rich PDAC tumors. Our study provides new insights into crosstalk among tumor cells, CAFs, and immune cells mediated by lactate and offers therapeutic strategies for targeting LDHA enzymatic activity in PDAC cells.