Miyara Shoval, Frenkel Shachaf, Mayo Avi, Gascard Philippe, Strasser Michael, Gibbs David, Weizman Eviatar, Shalom Itay Ben, Stein Yaniv, Pan Deng, Caruso Joseph A, Sangwan Veena, Bertos Nicholas, Berube Julie, Camilleri-Broet Sophie, Oikonomopoulos Spyridon, Djambazian Haig, Umansky Kfir Baruch, Elkahal Jacob, Mayer Shimrit, Fiset Pierre-Olivier, Ragoussis Jiannis, Adler Miri, Tzahor Eldad, Huang Sui, Ferri Lorenzo, Tlsty Thea D, Scherz-Shouval Ruth, Alon Uri
Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel.
Department of Pathology, University of California, San Francisco, CA, USA.
bioRxiv. 2025 Aug 25:2025.08.25.668405. doi: 10.1101/2025.08.25.668405.
The tumor microenvironment (TME) of chronic inflammation-associated cancers (CIACs) is shaped by cycles of injury and maladaptive repair, yet the principles organizing fibrotic stroma in these tumors remain unclear. Here, we applied the concept of hot versus cold fibrosis, originally credentialed in non-cancerous fibrosis of heart and kidney, to lung squamous cell carcinoma (LUSC), a prototypical CIAC. Single-cell transcriptomics of matched tumor and adjacent-normal tissue from 16 treatment-naive LUSC patients identified a cold fibrotic architecture in the LUSC TME: cancer-associated fibroblasts (CAFs) expanded and adopted myofibroblast and stress-response states, while macrophages were depleted. This macrophage-poor, CAF-rich stroma was maintained by CAF autocrine growth factor loops, including , and . In parallel, the immune compartment exhibited a hot tumor phenotype with abundant T and B cells, forming spatially distinct but molecularly engaged networks with CAFs. CAF gene programs typifying cold fibrosis in LUSC were conserved in other CIACs, including esophageal and gastric adenocarcinomas. These results redefine desmoplastic regions of tumors through the lens of a non-cancer fibrosis model, demonstrating that conserved stromal circuits constitute therapeutic vulnerabilities in CIACs.
慢性炎症相关癌症（CIAC）的肿瘤微环境（TME）由损伤和适应性不良修复的循环塑造而成，但这些肿瘤中组织纤维化基质的原理仍不清楚。在这里，我们将最初用于心脏和肾脏非癌性纤维化的热纤维化与冷纤维化概念应用于典型的CIAC——肺鳞状细胞癌（LUSC）。对16例未经治疗的LUSC患者的匹配肿瘤和邻近正常组织进行单细胞转录组学分析，发现LUSC的TME中存在冷纤维化结构：癌症相关成纤维细胞（CAF）增多并呈现肌成纤维细胞和应激反应状态，而巨噬细胞减少。这种巨噬细胞少、CAF丰富的基质由CAF自分泌生长因子环维持，包括 、 和 。同时，免疫区呈现热肿瘤表型，有丰富的T细胞和B细胞，与CAF形成空间上不同但分子上相互作用的网络。LUSC中代表冷纤维化的CAF基因程序在其他CIAC中也保守，包括食管和胃腺癌。这些结果通过非癌纤维化模型重新定义了肿瘤的促结缔组织增生区域，表明保守的基质回路构成了CIAC的治疗弱点。
