胰腺癌代谢应激下巨噬细胞增多症维持CAF亚型的特性，这一成果由桑福德伯纳姆普雷比斯医学发现研究所Cosimo Commisso小组经过不懈努力而取得。2025年7月24日出版的《癌细胞》杂志发表了这项成果。

在这项研究中，该研究组发现巨量红细胞增多症通过阻止炎症重编程来维持谷氨酰胺限制下的myCAF表型。他们的数据表明，代谢应激通过MEK-ERK信号传导诱导内在炎性CAF （iCAF）程序。该研究组发现，在体内阻断巨噬细胞作用可促进myCAF到iCAF的转变，重塑肿瘤基质。重要的是，由巨噬细胞增多抑制（包括iCAF富集、胶原减少、免疫细胞浸润和血管扩张）驱动的基质重塑使PDAC肿瘤对免疫治疗和化疗敏感。他们的研究结果表明，抑制巨噬细胞增多可促进炎症性、纤维化程度较低的肿瘤微环境，从而改善PDAC的治疗反应。

研究人员表示，胰腺导管腺癌（PDAC）肿瘤缺乏谷氨酰胺，肿瘤细胞和癌症相关成纤维细胞（CAFs）都依赖这种氨基酸来维持适应性并诱导巨噬细胞增生作为适应性反应。CAFs在塑造肿瘤微环境中起着关键作用，然而代谢应激的适应如何影响基质结构仍然是未知的。

附：英文原文

Title: Macropinocytosis maintains CAF subtype identity under metabolic stress in pancreatic cancer

Author: Yijuan Zhang, Li Ling, Rabi Murad, Swetha Maganti, Ambroise Manceau, Hannah A. Hetrick, Madelaine Neff, Cheska Marie Galapate, Shea F. Grenier, Florent Carrette, Karen Duong-Polk, Anindya Bagchi, David A. Scott, Yoav Altman, Jennifer L. Hope, Andrew M. Lowy, Linda M. Bradley, Cosimo Commisso

Issue&Volume: 2025-07-24

Abstract: Pancreatic ductal adenocarcinoma (PDAC) tumors are glutamine deficient, and both tumor cells and cancer-associated fibroblasts (CAFs) rely on this amino acid to maintain fitness and induce macropinocytosis as an adaptive response. CAFs play a critical role in sculpting the tumor microenvironment, yet how adaptations to metabolic stress impact the stromal architecture remains elusive. In this study, we find that macropinocytosis sustains the myCAF phenotype under glutamine limitation by preventing inflammatory reprogramming. Our data demonstrate that metabolic stress induces an intrinsic inflammatory CAF (iCAF) program through MEK-ERK signaling. We find that blocking macropinocytosis in vivo promotes myCAF-to-iCAF transitions, remodeling the tumor stroma. Importantly, stromal remodeling driven by macropinocytosis inhibition—including iCAF enrichment, collagen reduction, immune cell infiltration, and vascular expansion—sensitizes PDAC tumors to immunotherapy and chemotherapy. Our findings reveal that inhibiting macropinocytosis promotes an inflammatory, less fibrotic tumor microenvironment that can be leveraged to improve therapeutic responses in PDAC.

DOI: 10.1016/j.ccell.2025.06.021

Source: https://www.cell.com/cancer-cell/abstract/S1535-6108(25)00271-5