A fibroblast-centric network drives cold fibrosis in the tumor microenvironment of lung squamous cell carcinoma

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 TIMP1, INHBA, TGFB1, and GMFB. 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.