GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE300nnn/GSE300353/primaryOK200TranscriptomicsHomo sapiensExpression profiling by arrayhttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE300353GEOGSEfalseTranscriptomic analysis of CAFs with silencing of TERRA lnRNAThe tumor microenvironment is essential for cancer progression, yet the nuclear mechanisms that reprogram stromal fibroblasts into cancer-associated fibroblasts (CAFs) remain to be defined. Here, we identify a telomere-derived RNA–protein signaling axis that links genome integrity and fibroblast plasticity. We show that the long non-coding RNA TERRA, transcribed from telomeres, is upregulated in CAFs across multiple human skin cancers following loss of androgen receptor (AR) expression. Elevated TERRA enhances telomeric DNA damage and activates a CAF-specific transcriptional program. Through proteomic profiling, we identify the RNA-binding protein NONO as a critical TERRA effector. TERRA and NONO form nuclear complexes selectively in CAFs, while in normal fibroblasts NONO associates with AR. Disruption of the TERRA-NONO complex, either by genetic silencing or a small-molecule inhibitor of NONO, reverses CAF activation and suppresses tumor-stroma cells expansion in vitro and in vivo. These findings uncover a telomere-encoded mechanism of stromal reprogramming and identify the TERRA–NONO complex as a targetable point of vulnerability in the tumor microenvironment.2026/08/10GSE300353GSM9058976GSM9058978GSM9058977GSM9058979GSM9058981GSM905898023126300353Homo sapiens