Foxs1-mediated transformation of CD34+ fibroblast to myCAFs promotes tumor growth

Abstract Cancer-associated fibroblasts (CAFs) represent a major structural component of solid tumors and play crucial roles in cancer progression and drug resistance. However, their developmental origin, differentiation trajectory, and therapeutic potential remain poorly defined. Using advanced approaches—including inducible genetic lineage tracing, single-cell RNA sequencing, and spatial transcriptomic profiling—we identified a population of Cd34 + Pi16 + fibroblast progenitors (Cd34 + CAFs) in both melanoma and gastric cancer. We delineated their differentiation trajectory toward Acta2 + CAFs, driven by the upregulation of the transcription factor Foxs1. This work establishes the developmental origin of Acta2 + CAFs and experimentally validates the Cd34 + to Acta2 + transition. By reverse-matching the transcriptional signatures of Acta2 + CAF differentiation with the CMap/LINCS L1000 drug perturbation database, we identified four small-molecule candidates predicted to inhibit tumor-induced Foxs1 upregulation. These compounds effectively suppressed Cd34 + CAF differentiation, maintaining the progenitor-like Cd34 + state. Collectively, this study proposes a novel antitumor strategy that targets CAF lineage development to restrain tumor progression.